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The edits describe in detail the discovery, tissue distribution, secretion, structure, functions, and medical relevance of mammalian Peptidoglycan Recognition Protein 2 and include references to original research articles. Relevant review articles are listed in the Further reading section.
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'''Peptidoglycan recognition protein 2''' '''(PGLYRP2''') is an [[enzyme]] (EC 3.5.1.28), [[N-acetylmuramoyl-L-alanine amidase]] (NAMLAA), that hydrolyzes [[Bacteria|bacterial]] [[cell wall]] [[peptidoglycan]] and is encoded by the ''PGLYRP2'' [[gene]].<ref name=":0">{{Cite journal|last=Liu|first=C.|last2=Xu|first2=Z.|last3=Gupta|first3=D.|last4=Dziarski|first4=R.|date=2001-09-14|title=Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules|url=https://pubmed.ncbi.nlm.nih.gov/11461926|journal=The Journal of Biological Chemistry|volume=276|issue=37|pages=34686–34694|doi=10.1074/jbc.M105566200|issn=0021-9258|pmid=11461926}}</ref><ref name=":1">{{Cite journal|last=Kibardin|first=A. V.|last2=Mirkina|first2=I. I.|last3=Korneeva|first3=E. A.|last4=Gnuchev|first4=N. V.|last5=Georgiev|first5=G. P.|last6=Kiselev|first6=S. L.|date=2000-05|title=Molecular cloning of a new mouse gene tagL containing a lysozyme-like domain|url=https://pubmed.ncbi.nlm.nih.gov/10935177|journal=Doklady biochemistry: proceedings of the Academy of Sciences of the USSR, Biochemistry section|volume=372|issue=1-6|pages=103–105|issn=0012-4958|pmid=10935177}}</ref><ref name=":2">{{Cite journal|last=Gelius|first=Eva|last2=Persson|first2=Carina|last3=Karlsson|first3=Jenny|last4=Steiner|first4=Håkan|date=2003-07-11|title=A mammalian peptidoglycan recognition protein with N-acetylmuramoyl-L-alanine amidase activity|url=https://pubmed.ncbi.nlm.nih.gov/12821140|journal=Biochemical and Biophysical Research Communications|volume=306|issue=4|pages=988–994|doi=10.1016/s0006-291x(03)01096-9|issn=0006-291X|pmid=12821140}}</ref><ref name=":3">{{Cite journal|last=Wang|first=Zheng-Ming|last2=Li|first2=Xinna|last3=Cocklin|first3=Ross R.|last4=Wang|first4=Minhui|last5=Wang|first5=Mu|last6=Fukase|first6=Koichi|last7=Inamura|first7=Seiichi|last8=Kusumoto|first8=Shoichi|last9=Gupta|first9=Dipika|last10=Dziarski|first10=Roman|date=2003-12-05|title=Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-L-alanine amidase|url=https://pubmed.ncbi.nlm.nih.gov/14506276|journal=The Journal of Biological Chemistry|volume=278|issue=49|pages=49044–49052|doi=10.1074/jbc.M307758200|issn=0021-9258|pmid=14506276}}</ref><ref>{{Cite web|title=PGLYRP2 peptidoglycan recognition protein 2 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=114770|access-date=2020-11-02|website=www.ncbi.nlm.nih.gov}}</ref>{{Infobox_gene}}
{{Infobox_gene}}
''PGLYRP2'' is a [[gene]] encoding a protein with [[N-acetylmuramoyl-L-alanine amidase]] activity.<ref name="pmid11461926">{{cite journal | vauthors = Liu C, Xu Z, Gupta D, Dziarski R | title = Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules | journal = J Biol Chem | volume = 276 | issue = 37 | pages = 34686–94 |date=Sep 2001 | pmid = 11461926 | pmc = | doi = 10.1074/jbc.M105566200 | doi-access = free }}</ref><ref name="pmid12669421">{{cite journal | vauthors = Kibardin AV, Mirkina II, Zakeeva IR, Baranova EV, Georgiev GP, Kiselev SL | title = [Expression analysis of proteins encoded by genes of the tag7/tagL (PGRP-S,L) family in human peripheral blood cells] | journal = Genetika | volume = 39 | issue = 2 | pages = 244–9 |date=Apr 2003 | pmid = 12669421 | pmc = | doi = }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PGLYRP2 peptidoglycan recognition protein 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=114770| accessdate = }}</ref>


== Discovery ==
Peptidoglycan recognition proteins, such as PGRPL, are part of the innate immune system and recognize peptidoglycan, a ubiquitous component of bacterial cell walls.[supplied by OMIM]<ref name="entrez"/>
The ''N''-acetylmuramoyl-L-alanine amidase enzymatic activity was first observed in human and mouse [[Serum (blood)|serum]] in 1981 by Branko Ladešić and coworkers.<ref name=":4">{{Cite journal|last=Ladesić|first=B.|last2=Tomasić|first2=J.|last3=Kveder|first3=S.|last4=Hrsak|first4=I.|date=1981-11-18|title=The metabolic fate of 14C-labeled immunoadjuvant peptidoglycan monomer. II. In vitro studies|url=https://pubmed.ncbi.nlm.nih.gov/6118181|journal=Biochimica Et Biophysica Acta|volume=678|issue=1|pages=12–17|doi=10.1016/0304-4165(81)90042-8|issn=0006-3002|pmid=6118181}}</ref> The enzyme (abbreviated NAMLAA) was then purified from human serum by this<ref name=":5">{{Cite journal|last=Valinger|first=Z.|last2=Ladesić|first2=B.|last3=Tomasić|first3=J.|date=1982-02-04|title=Partial purification and characterization of N-acetylmuramyl-L-alanine amidase from human and mouse serum|url=https://pubmed.ncbi.nlm.nih.gov/6120007|journal=Biochimica Et Biophysica Acta|volume=701|issue=1|pages=63–71|doi=10.1016/0167-4838(82)90313-2|issn=0006-3002|pmid=6120007}}</ref> and other groups.<ref name=":6">{{Cite journal|last=Mollner|first=S.|last2=Braun|first2=V.|date=1984-12|title=Murein hydrolase (N-acetyl-muramyl-L-alanine amidase) in human serum|url=https://pubmed.ncbi.nlm.nih.gov/6152147|journal=Archives of Microbiology|volume=140|issue=2-3|pages=171–177|doi=10.1007/BF00454921|issn=0302-8933|pmid=6152147}}</ref><ref name=":7">{{Cite journal|last=Vanderwinkel|first=E.|last2=de Vlieghere|first2=M.|last3=de Pauw|first3=P.|last4=Cattalini|first4=N.|last5=Ledoux|first5=V.|last6=Gigot|first6=D.|last7=ten Have|first7=J. P.|date=1990-07-06|title=Purification and characterization of N-acetylmuramoyl-L-alanine amidase from human serum|url=https://pubmed.ncbi.nlm.nih.gov/1974148|journal=Biochimica Et Biophysica Acta|volume=1039|issue=3|pages=331–338|doi=10.1016/0167-4838(90)90267-j|issn=0006-3002|pmid=1974148}}</ref><ref name=":8">{{Cite journal|last=De Pauw|first=P.|last2=Neyt|first2=C.|last3=Vanderwinkel|first3=E.|last4=Wattiez|first4=R.|last5=Falmagne|first5=P.|date=1995-06|title=Characterization of human serum N-acetylmuramyl-L-alanine amidase purified by affinity chromatography|url=https://pubmed.ncbi.nlm.nih.gov/7663175|journal=Protein Expression and Purification|volume=6|issue=3|pages=371–378|doi=10.1006/prep.1995.1049|issn=1046-5928|pmid=7663175}}</ref><ref name=":9">{{Cite journal|last=Hoijer|first=M. A.|last2=Melief|first2=M. J.|last3=Keck|first3=W.|last4=Hazenberg|first4=M. P.|date=1996-02-09|title=Purification and characterization of N-acetylmuramyl-L-alanine amidase from human plasma using monoclonal antibodies|url=https://pubmed.ncbi.nlm.nih.gov/8605233|journal=Biochimica Et Biophysica Acta|volume=1289|issue=1|pages=57–64|doi=10.1016/0304-4165(95)00136-0|issn=0006-3002|pmid=8605233}}</ref> The sequence of 15 N-terminal amino acids of NAMLAA was identified,<ref name=":8" /> but the [[Complementary DNA|cDNA]] for the [[protein]] was not cloned and the gene encoding NAMLAA was not known.


In 2000, Dan Hultmark and coworkers discovered a family of 12 [[Peptidoglycan recognition protein|Peptidoglycan Recognition Protein]] (PGRP) genes in [[Drosophila melanogaster|''Drosophila'' ''melanogaster'']] and by homology searches of available human and mouse sequences predicted the presence of long forms of human and mouse PGRPs, which they named PGRP-L by analogy to long forms of insect PGRPs.<ref>{{Cite journal|last=Werner|first=T.|last2=Liu|first2=G.|last3=Kang|first3=D.|last4=Ekengren|first4=S.|last5=Steiner|first5=H.|last6=Hultmark|first6=D.|date=2000-12-05|title=A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster|url=https://pubmed.ncbi.nlm.nih.gov/11106397|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=25|pages=13772–13777|doi=10.1073/pnas.97.25.13772|issn=0027-8424|pmc=PMC17651|pmid=11106397}}</ref>
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==See also==

In 2001, Roman Dziarski and coworkers discovered and cloned three human PGRPs, named PGRP-L, PGRP-Iα, and PGRP-Iβ (for long and intermediate size transcripts),<ref name=":0" /> and established that human [[genome]] codes for a family of 4 PGRPs: PGRP-S (short PGRP)<ref>{{Cite journal|last=Kang|first=D.|last2=Liu|first2=G.|last3=Lundström|first3=A.|last4=Gelius|first4=E.|last5=Steiner|first5=H.|date=1998-08-18|title=A peptidoglycan recognition protein in innate immunity conserved from insects to humans|url=https://pubmed.ncbi.nlm.nih.gov/9707603|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=95|issue=17|pages=10078–10082|doi=10.1073/pnas.95.17.10078|issn=0027-8424|pmc=PMC21464|pmid=9707603}}</ref> and PGRP-L, PGRP-Iα, and PGRP-Iβ.<ref name=":0" /> Subsequently, the Human Genome Organization Gene Nomenclature Committee changed the gene symbols of PGRP-S, PGRP-L, PGRP-Iα, and PGRP-Iβ to ''PGLYRP1'' ([[peptidoglycan recognition protein 1]]), ''PGLYRP2'' ([[peptidoglycan recognition protein 2]]), ''PGLYRP3'' ([[peptidoglycan recognition protein 3]]), and ''PGLYRP4'' ([[peptidoglycan recognition protein 4]]), respectively, and this nomenclature is currently also used for other [[Mammal|mammalian]] PGRPs. Sergei Kiselev and coworkers also independently cloned mouse PGLYRP2 (which they named TagL).<ref name=":1" /><ref>{{Cite journal|last=Kibardin|first=A. V.|last2=Mirkina|first2=I. I.|last3=Baranova|first3=E. V.|last4=Zakeyeva|first4=I. R.|last5=Georgiev|first5=G. P.|last6=Kiselev|first6=S. L.|date=2003-02-14|title=The differentially spliced mouse tagL gene, homolog of tag7/PGRP gene family in mammals and Drosophila, can recognize Gram-positive and Gram-negative bacterial cell wall independently of T phage lysozyme homology domain|url=https://pubmed.ncbi.nlm.nih.gov/12559914|journal=Journal of Molecular Biology|volume=326|issue=2|pages=467–474|doi=10.1016/s0022-2836(02)01401-8|issn=0022-2836|pmid=12559914}}</ref>

In 2003 Håkan Steiner and coworkers<ref name=":2" /> and Roman Dziarski and coworkers<ref name=":3" /> discovered that mouse<ref name=":2" /> and human<ref name=":3" /> PGLYRP2 (PGRP-L) proteins encoded by the mouse and human ''PGLYRP2'' genes are ''N''-acetylmuramoyl-L-alanine amidases. Recombinant and native human PGLYRP2 proteins were then further shown to be identical with the previously identified and purified serum NAMLAA.<ref name=":10">{{Cite journal|last=Zhang|first=Yinong|last2=van der Fits|first2=Leslie|last3=Voerman|first3=Jane S.|last4=Melief|first4=Marie-Jose|last5=Laman|first5=Jon D.|last6=Wang|first6=Mu|last7=Wang|first7=Haitao|last8=Wang|first8=Minhui|last9=Li|first9=Xinna|last10=Walls|first10=Chad D.|last11=Gupta|first11=Dipika|date=2005-08-31|title=Identification of serum N-acetylmuramoyl-l-alanine amidase as liver peptidoglycan recognition protein 2|url=https://pubmed.ncbi.nlm.nih.gov/16054449|journal=Biochimica Et Biophysica Acta|volume=1752|issue=1|pages=34–46|doi=10.1016/j.bbapap.2005.07.001|issn=0006-3002|pmid=16054449}}</ref>

== Tissue distribution and secretion ==
Human and mouse PGLYRP2 is constitutively expressed in the adult and fetal [[liver]], from where it is secreted into the [[blood]].<ref name=":0" /><ref name=":2" /><ref name=":10" /><ref name=":11">{{Cite journal|last=Xu|first=Min|last2=Wang|first2=Zhien|last3=Locksley|first3=Richard M.|date=2004-09|title=Innate immune responses in peptidoglycan recognition protein L-deficient mice|url=https://pubmed.ncbi.nlm.nih.gov/15340057|journal=Molecular and Cellular Biology|volume=24|issue=18|pages=7949–7957|doi=10.1128/MCB.24.18.7949-7957.2004|issn=0270-7306|pmc=PMC515053|pmid=15340057}}</ref><ref name=":12">{{Cite journal|last=Li|first=Xinna|last2=Wang|first2=Shiyong|last3=Wang|first3=Haitao|last4=Gupta|first4=Dipika|date=2006-07-28|title=Differential expression of peptidoglycan recognition protein 2 in the skin and liver requires different transcription factors|url=https://pubmed.ncbi.nlm.nih.gov/16714290|journal=The Journal of Biological Chemistry|volume=281|issue=30|pages=20738–20748|doi=10.1074/jbc.M601017200|issn=0021-9258|pmid=16714290}}</ref> PGLYRP2 (NAMLAA) is present in human plasma at 100 to 200 µg/ml<ref name=":9" /><ref name=":13">{{Cite journal|last=Vanderwinkel|first=E.|last2=de Pauw|first2=P.|last3=Philipp|first3=D.|last4=Ten Have|first4=J. P.|last5=Bainter|first5=K.|date=1995-02|title=The human and mammalian N-acetylmuramyl-L-alanine amidase: distribution, action on different bacterial peptidoglycans, and comparison with the human lysozyme activities|url=https://pubmed.ncbi.nlm.nih.gov/7551813|journal=Biochemical and Molecular Medicine|volume=54|issue=1|pages=26–32|doi=10.1006/bmme.1995.1004|issn=1077-3150|pmid=7551813}}</ref> and at lower concentrations in saliva, milk, [[cerebrospinal fluid]], and [[synovial fluid]].<ref name=":13" /> PGLYRP2 is also expressed to a much lower level in the colon, [[Lymph node|lymph nodes]], [[spleen]], [[thymus]], heart, and [[Granulocyte|polymorphonuclear leukocyte]] granules.<ref name=":0" /><ref>{{Cite journal|last=Hoijer|first=M. A.|last2=Melief|first2=M. J.|last3=Calafat|first3=J.|last4=Roos|first4=D.|last5=van den Beemd|first5=R. W.|last6=van Dongen|first6=J. J.|last7=Hazenberg|first7=M. P.|date=1997-08-01|title=Expression and intracellular localization of the human N-acetylmuramyl-L-alanine amidase, a bacterial cell wall-degrading enzyme|url=https://pubmed.ncbi.nlm.nih.gov/9242559|journal=Blood|volume=90|issue=3|pages=1246–1254|issn=0006-4971|pmid=9242559}}</ref><ref>{{Cite journal|last=Hoijer|first=M. A.|last2=de Groot|first2=R.|last3=van Lieshout|first3=L.|last4=Jacobs|first4=B. C.|last5=Melief|first5=M. J.|last6=Hazenberg|first6=M. P.|date=1998-01|title=Differences in N-acetylmuramyl-L-alanine amidase and lysozyme in serum and cerebrospinal fluid of patients with bacterial meningitis|url=https://pubmed.ncbi.nlm.nih.gov/9419176|journal=The Journal of Infectious Diseases|volume=177|issue=1|pages=102–106|doi=10.1086/513815|issn=0022-1899|pmid=9419176}}</ref> PGLYRP2 is differentially expressed in the developing brain and this expression is influenced by the intestinal [[microbiome]].<ref name=":14">{{Cite journal|last=Arentsen|first=T.|last2=Qian|first2=Y.|last3=Gkotzis|first3=S.|last4=Femenia|first4=T.|last5=Wang|first5=T.|last6=Udekwu|first6=K.|last7=Forssberg|first7=H.|last8=Diaz Heijtz|first8=R.|date=02 2017|title=The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior|url=https://pubmed.ncbi.nlm.nih.gov/27843150|journal=Molecular Psychiatry|volume=22|issue=2|pages=257–266|doi=10.1038/mp.2016.182|issn=1476-5578|pmc=5285465|pmid=27843150}}</ref> Bacteria and [[Cytokine|cytokines]] induce low level of PGLYRP2 expression in the [[skin]] and [[Gastrointestinal tract|gastrointestinal]] and oral [[Epithelium|epithelial]] [[Cell (biology)|cells]],<ref name=":12" /><ref name=":15">{{Cite journal|last=Wang|first=Haitao|last2=Gupta|first2=Dipika|last3=Li|first3=Xinna|last4=Dziarski|first4=Roman|date=2005-11|title=Peptidoglycan recognition protein 2 (N-acetylmuramoyl-L-Ala amidase) is induced in keratinocytes by bacteria through the p38 kinase pathway|url=https://pubmed.ncbi.nlm.nih.gov/16239516|journal=Infection and Immunity|volume=73|issue=11|pages=7216–7225|doi=10.1128/IAI.73.11.7216-7225.2005|issn=0019-9567|pmc=1273900|pmid=16239516}}</ref><ref>{{Cite journal|last=Lu|first=Xiaofeng|last2=Wang|first2=Minhui|last3=Qi|first3=Jin|last4=Wang|first4=Haitao|last5=Li|first5=Xinna|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2006-03-03|title=Peptidoglycan recognition proteins are a new class of human bactericidal proteins|url=https://pubmed.ncbi.nlm.nih.gov/16354652|journal=The Journal of Biological Chemistry|volume=281|issue=9|pages=5895–5907|doi=10.1074/jbc.M511631200|issn=0021-9258|pmid=16354652}}</ref><ref>{{Cite journal|last=Uehara|first=A.|last2=Sugawara|first2=Y.|last3=Kurata|first3=S.|last4=Fujimoto|first4=Y.|last5=Fukase|first5=K.|last6=Kusumoto|first6=S.|last7=Satta|first7=Y.|last8=Sasano|first8=T.|last9=Sugawara|first9=S.|last10=Takada|first10=H.|date=2005-05|title=Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like receptors, NOD1 and NOD2 in human oral epithelial cells|url=https://pubmed.ncbi.nlm.nih.gov/15839897|journal=Cellular Microbiology|volume=7|issue=5|pages=675–686|doi=10.1111/j.1462-5822.2004.00500.x|issn=1462-5814|pmid=15839897}}</ref><ref name=":16">{{Cite journal|last=Scholz|first=Glen M.|last2=Heath|first2=Jacqueline E.|last3=Aw|first3=Jiamin|last4=Reynolds|first4=Eric C.|date=09 2018|title=Regulation of the Peptidoglycan Amidase PGLYRP2 in Epithelial Cells by Interleukin-36γ|url=https://pubmed.ncbi.nlm.nih.gov/29914927|journal=Infection and Immunity|volume=86|issue=9|doi=10.1128/IAI.00384-18|issn=1098-5522|pmc=6105881|pmid=29914927}}</ref> and also in [[Gastrointestinal tract|intestinal]] [[Intraepithelial lymphocyte|intraepithelial T lymphocytes]], [[Dendritic cell|dendritic cells]], NK ([[Natural killer cell|natural killer]]) cells, and inflammatory [[Macrophage|macrophages]].<ref name=":17">{{Cite journal|last=Duerr|first=C. U.|last2=Salzman|first2=N. H.|last3=Dupont|first3=A.|last4=Szabo|first4=A.|last5=Normark|first5=B. H.|last6=Normark|first6=S.|last7=Locksley|first7=R. M.|last8=Mellroth|first8=P.|last9=Hornef|first9=M. W.|date=2011-05|title=Control of intestinal Nod2-mediated peptidoglycan recognition by epithelium-associated lymphocytes|url=https://pubmed.ncbi.nlm.nih.gov/20980996|journal=Mucosal Immunology|volume=4|issue=3|pages=325–334|doi=10.1038/mi.2010.71|issn=1935-3456|pmid=20980996}}</ref><ref name=":18">{{Cite journal|last=Lee|first=Jooeun|last2=Geddes|first2=Kaoru|last3=Streutker|first3=Catherine|last4=Philpott|first4=Dana J.|last5=Girardin|first5=Stephen E.|date=2012-08|title=Role of mouse peptidoglycan recognition protein PGLYRP2 in the innate immune response to Salmonella enterica serovar Typhimurium infection in vivo|url=https://pubmed.ncbi.nlm.nih.gov/22615249|journal=Infection and Immunity|volume=80|issue=8|pages=2645–2654|doi=10.1128/IAI.00168-12|issn=1098-5522|pmc=3434585|pmid=22615249}}</ref> Some mammals, e.g. pigs, express multiple [[Alternative splicing|splice forms]] of PGLYRP2 with differential expression.<ref>{{Cite journal|last=Sang|first=Yongming|last2=Ramanathan|first2=Balaji|last3=Ross|first3=Christopher R.|last4=Blecha|first4=Frank|date=2005-11|title=Gene silencing and overexpression of porcine peptidoglycan recognition protein long isoforms: involvement in beta-defensin-1 expression|url=https://pubmed.ncbi.nlm.nih.gov/16239507|journal=Infection and Immunity|volume=73|issue=11|pages=7133–7141|doi=10.1128/IAI.73.11.7133-7141.2005|issn=0019-9567|pmc=1273832|pmid=16239507}}</ref>

Bacteria and cytokines induce expression of PGLYRP2 in epithelial cells through the [[P38 mitogen-activated protein kinases|p38 mitogen activated protein kinase]] (MAPK) and [[IRAK1]] (interleukin-1 receptor-associated kinase 1) signaling pathways.<ref name=":15" /><ref name=":16" /> Constitutive and induced expression of PGLYRP2 is controlled by different [[Transcription factor|transcription factors]] whose binding sequences are located in different regions of the ''PGLYRP2'' [[Promoter (genetics)|promoter]].<ref name=":12" /> Constitutive expression of ''PGLYRP2'' in [[Hepatocyte|hepatocytes]] is regulated by transcription factors [[C-jun|c-Jun]] and ATF2 ([[activating transcription factor 2]]) through sequences in the proximal region of the promoter.<ref name=":12" /> Induced expression of ''PGLYRP2'' in [[Keratinocyte|keratinocytes]] is regulated by transcription factors [[NF-κB]] (nuclear factor kappa-light-chain-enhancer of activated B cells) and [[Sp1 transcription factor|Sp1]] (specificity protein 1) through sequences in the distal region of the promoter.<ref name=":12" />

== Structure ==
PGLYRP2 has one canonical carboxy-terminal catalytic [[N-acetylmuramoyl-L-alanine amidase|peptidoglycan-binding type 2 amidase domain]] (also known as a PGRP domain) with predicted peptidoglycan-binding and catalytic cleft with walls formed by α-helices and the floor by a β-sheet.<ref name=":0" /><ref name=":2" /><ref name=":19">{{Cite journal|last=Zulfiqar|first=Fareeha|last2=Hozo|first2=Iztok|last3=Rangarajan|first3=Sneha|last4=Mariuzza|first4=Roy A.|last5=Dziarski|first5=Roman|last6=Gupta|first6=Dipika|date=2013|title=Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease|url=https://pubmed.ncbi.nlm.nih.gov/23840689|journal=PloS One|volume=8|issue=6|pages=e67393|doi=10.1371/journal.pone.0067393|issn=1932-6203|pmc=3686734|pmid=23840689}}</ref> PGLYRP2 also has a long N-terminal segment that comprises two thirds of the PGLYRP2 sequence, has two [[Hydrophobe|hydrophobic]] regions, is not found in other mammalian PGLYRP1, PGLYRP3, and PGLYRP4 and in [[invertebrate]] PGRPs, and is unique with no identifiable functional motifs or domains.<ref name=":0" /><ref name=":2" /><ref name=":19" /> The C-terminal segment is also longer than in other mammalian PGLYRPs.<ref name=":0" /><ref name=":2" /><ref name=":19" /> PGLYRP2 has two pairs of [[Cysteine|cysteines]] in the PGRP domain that are conserved in all human PGRPs and are predicted to form two [[disulfide]] bonds.<ref name=":0" /> Human PGLYRP2 is [[Glycosylation|glycosylated]]<ref name=":6" /><ref name=":8" /> and secreted,<ref name=":5" /><ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9" /><ref name=":10" /><ref name=":11" /> and forms non-disulfide-linked homodimers.<ref name=":8" />

PGLYRP2, similar to all other amidase-active PGRPs (invertebrate and [[vertebrate]]) has a conserved Zn<sup>2+</sup>-binding site in the peptidoglycan-binding cleft, which is also present in [[bacteriophage]] type 2 amidases and consists of two [[Histidine|histidines]], one [[tyrosine]], and one cysteine (His411, Tyr447, His522, Cys530 in human PGLYRP2).<ref name=":3" />

== Functions ==
The PGLYRP2 protein plays an important role in the [[Innate immune system|innate immune responses]].

=== '''Peptidoglycan binding and hydrolysis''' ===
PGLYRP2 is an enzyme (EC 3.5.1.28), ''N''-acetylmuramoyl-L-alanine amidase, that binds and hydrolyzes bacterial cell wall peptidoglycan.<ref name=":0" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9" /> Peptidoglycan is the main component of bacterial cell wall and is a polymer of β(1-4)-linked [[N-Acetylglucosamine|''N''-acetylglucosamine]] (GlcNAc) and [[N-Acetylmuramic acid|''N''-acetylmuramic acid]] (MurNAc) with MurNAc-attached short [[Peptide|peptides]], typically composed of alternating L and D [[Amino acid|amino acids]], that cross-link the adjacent [[polysaccharide]] chains.

PGLYRP2 hydrolyzes the amide bond between the MurNAc and L-Ala, the first amino acid in the stem peptide.<ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" /> This hydrolysis separates the crosslinking peptides from the polysaccharide chains and solubilizes cross-linked bacterial peptidoglycan into uncross-linked polysaccharide chains.<ref name=":3" /> The minimal peptidoglycan fragment hydrolyzed by PGLYRP2 is MurNAc-tripeptide.<ref name=":3" />

The peptidoglycan-binding site, which is also the amidase catalytic domain, is located in the C-terminal PGRP domain. This PGRP domain is sufficient for the enzymatic activity of PGLYRP2, although this activity of the isolated C-terminal fragment is diminished compared with the entire PGLYRP2 molecule.<ref name=":3" /> Zn<sup>2+</sup> and Zn<sup>2+</sup>-binding amino acids (His411, Tyr447, and Cys530 in human PGLYRP2) are required for the amidase activity.<ref name=":3" /> Cys419 in human PGLYRP2, which is broadly conserved in invertebrate and vertebrate PRGPs, forms a disulfide bond with Cys425 (in human PGLYRP2) and is required for the amidase activity, as this disulfide bond is essential for the structural integrity of the PGRP domain.<ref name=":3" /> Cys530 is conserved in all amidase-active vertebrate and invertebrate PGRPs, whereas non-catalytic PGRPs (including mammalian PGLYRP1, PGLYRP3, and PGLYRP4) have [[serine]] in this position,<ref name=":0" /> and thus the presence of Cys or Ser in this position can be used to predict amidase activity of PGRPs.<ref name=":3" /> However, Cys530 and seven other amino acids that are all required for the amidase activity of PGRPs are not sufficient for the amidase activity, which requires additional so far unidentified amino acids.<ref name=":3" />

=== '''Defense against infections''' ===
PGLYRP2 plays a limited role in host defense against [[Infection|infections]]. ''PGLYRP2''-deficient mice are more sensitive to ''[[Pseudomonas aeruginosa]]''-induced keratitis<ref name=":20">{{Cite journal|last=Gowda|first=Ranjita N.|last2=Redfern|first2=Rachel|last3=Frikeche|first3=Jihane|last4=Pinglay|first4=Sudarshan|last5=Foster|first5=James William|last6=Lema|first6=Carolina|last7=Cope|first7=Leslie|last8=Chakravarti|first8=Shukti|date=2015|title=Functions of Peptidoglycan Recognition Proteins (Pglyrps) at the Ocular Surface: Bacterial Keratitis in Gene-Targeted Mice Deficient in Pglyrp-2, -3 and -4|url=https://pubmed.ncbi.nlm.nih.gov/26332373|journal=PloS One|volume=10|issue=9|pages=e0137129|doi=10.1371/journal.pone.0137129|issn=1932-6203|pmc=4558058|pmid=26332373}}</ref> and ''Streptococcus pneumoniae''-induced pneumonia and sepsis.<ref name=":21">{{Cite journal|last=Dabrowski|first=Alexander N.|last2=Conrad|first2=Claudia|last3=Behrendt|first3=Ulrike|last4=Shrivastav|first4=Anshu|last5=Baal|first5=Nelli|last6=Wienhold|first6=Sandra M.|last7=Hackstein|first7=Holger|last8=N'Guessan|first8=Philippe D.|last9=Aly|first9=Sahar|last10=Reppe|first10=Katrin|last11=Suttorp|first11=Norbert|date=2019|title=Peptidoglycan Recognition Protein 2 Regulates Neutrophil Recruitment Into the Lungs After Streptococcus pneumoniae Infection|url=https://pubmed.ncbi.nlm.nih.gov/30837960|journal=Frontiers in Microbiology|volume=10|pages=199|doi=10.3389/fmicb.2019.00199|issn=1664-302X|pmc=6389715|pmid=30837960}}</ref> However, ''PGLYRP2''-deficient mice did not show a changed susceptibility to systemic ''Escherichia coli'', ''Staphylococcus aureus'', and ''Candida'' ''albicans'' infections<ref name=":11" /> or intestinal ''Salmonella enterica'' infection,<ref name=":18" /> although the latter was accompanied by increased inflammation in the cecum.<ref name=":17" />

Although PGLYRP2 is not directly bacteriolytic,<ref name=":3" /> it has antibacterial activity against both Gram-positive and Gram-negative bacteria and ''Chlamydia''.<ref>{{Cite journal|last=Bobrovsky|first=Pavel|last2=Manuvera|first2=Valentin|last3=Polina|first3=Nadezhda|last4=Podgorny|first4=Oleg|last5=Prusakov|first5=Kirill|last6=Govorun|first6=Vadim|last7=Lazarev|first7=Vassili|date=07 2016|title=Recombinant Human Peptidoglycan Recognition Proteins Reveal Antichlamydial Activity|url=https://pubmed.ncbi.nlm.nih.gov/27160295|journal=Infection and Immunity|volume=84|issue=7|pages=2124–2130|doi=10.1128/IAI.01495-15|issn=1098-5522|pmc=4936355|pmid=27160295}}</ref>

=== '''Maintaining microbiome''' ===
Mouse PGLYRP2 plays a role in maintaining healthy microbiome, as ''PGLYRP2''-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to [[colitis]].<ref name=":22">{{Cite journal|last=Saha|first=Sukumar|last2=Jing|first2=Xuefang|last3=Park|first3=Shin Yong|last4=Wang|first4=Shiyong|last5=Li|first5=Xinna|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2010-08-19|title=Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma|url=https://pubmed.ncbi.nlm.nih.gov/20709292|journal=Cell Host & Microbe|volume=8|issue=2|pages=147–162|doi=10.1016/j.chom.2010.07.005|issn=1934-6069|pmc=2998413|pmid=20709292}}</ref><ref>{{Cite journal|last=Dziarski|first=Roman|last2=Park|first2=Shin Yong|last3=Kashyap|first3=Des Raj|last4=Dowd|first4=Scot E.|last5=Gupta|first5=Dipika|date=2016|title=Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice|url=https://pubmed.ncbi.nlm.nih.gov/26727498|journal=PloS One|volume=11|issue=1|pages=e0146162|doi=10.1371/journal.pone.0146162|issn=1932-6203|pmc=4699708|pmid=26727498}}</ref>

=== '''Effects on inflammation''' ===
PGLYRP2 directly and indirectly affects [[inflammation]] and plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine, skin, joints, and brain.

Hydrolysis of peptidoglycan by PGLYRP2 diminishes peptidoglycan’s pro-inflammatory activity.<ref name=":17" /><ref>{{Cite journal|last=Hoijer|first=M. A.|last2=Melief|first2=M. J.|last3=Debets|first3=R.|last4=Hazenberg|first4=M. P.|date=1997-12|title=Inflammatory properties of peptidoglycan are decreased after degradation by human N-acetylmuramyl-L-alanine amidase|url=https://pubmed.ncbi.nlm.nih.gov/9459617|journal=European Cytokine Network|volume=8|issue=4|pages=375–381|issn=1148-5493|pmid=9459617}}</ref> This effect is likely due to amidase activity of PGLYRP2, which separates the stem peptide from MurNAc in peptidoglycan and destroys the motif required for the peptidoglycan-induced activation of [[NOD2]] (nucleotide-binding oligomerization domain-containing protein 2), one of the proinflammatory peptidoglycan receptors.<ref name=":17" />

''PGLYRP2''-deficient mice are more susceptible than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP2 protects mice from DSS-induced colitis.<ref name=":22" /> Intestinal microbiome is important for this protection, because this increased sensitivity to colitis could be transferred to wild type [[Germ-free animal|germ-free]] mice by microbiome transplant from ''PGLYRP2''-deficient mice.<ref name=":22" />

''PGLYRP2''-deficient mice are more susceptible than wild type mice to the development of experimentally induced [[psoriasis]]-like inflammation,<ref name=":23">{{Cite journal|last=Park|first=Shin Yong|last2=Gupta|first2=Dipika|last3=Hurwich|first3=Risa|last4=Kim|first4=Chang H.|last5=Dziarski|first5=Roman|date=2011-12-01|title=Peptidoglycan recognition protein Pglyrp2 protects mice from psoriasis-like skin inflammation by promoting regulatory T cells and limiting Th17 responses|url=https://pubmed.ncbi.nlm.nih.gov/22048773|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=187|issue=11|pages=5813–5823|doi=10.4049/jimmunol.1101068|issn=1550-6606|pmc=3221838|pmid=22048773}}</ref> which indicates that PGLYRP2 is anti-inflammatory and protects mice from this type of skin inflammation. This pro-inflammatory effect is due to increased numbers and activity of [[T helper 17 cell|T helper 17]] (Th17) cells and decreased numbers of [[T regulatory cell|T regulatory]] (Treg) cells.<ref name=":23" /> ''PGLYRP2''-deficient mice are more susceptible than wild type mice to ''[[Salmonella enterica]]''-induced intestinal inflammation,<ref name=":18" /> which indicates that PGLYRP2 also has anti-inflammatory effect in the intestinal tract.

However, PGLYRP2 can also have opposite effects. ''PGLYRP2''-deficient mice are more resistant than wild type mice to the development of [[arthritis]] induced by systemic administration of peptidoglycan or MurNAc-L-Ala-D-isoGln peptidoglycan fragment ([[muramyl dipeptide]], MDP).<ref name=":24">{{Cite journal|last=Saha|first=Sukumar|last2=Qi|first2=Jin|last3=Wang|first3=Shiyong|last4=Wang|first4=Minhui|last5=Li|first5=Xinna|last6=Kim|first6=Yun-Gi|last7=Núñez|first7=Gabriel|last8=Gupta|first8=Dipika|last9=Dziarski|first9=Roman|date=2009-02-19|title=PGLYRP-2 and Nod2 are both required for peptidoglycan-induced arthritis and local inflammation|url=https://pubmed.ncbi.nlm.nih.gov/19218085|journal=Cell Host & Microbe|volume=5|issue=2|pages=137–150|doi=10.1016/j.chom.2008.12.010|issn=1934-6069|pmc=2671207|pmid=19218085}}</ref> In this model, PGLYRP2 is required for the production of [[Chemokine|chemokines]] and cytokines that attract [[Neutrophil|neutrophils]] to the arthritic joints.<ref name=":24" /> ''PGLYRP2''-deficient mice are also more resistant than wild type mice to bacterially induced [[keratitis]]<ref name=":20" /> and inflammation in ''[[Streptococcus pneumoniae]]''-induced lung infection.<ref name=":21" /> These results indicate that under certain conditions PGLYRP2 has pro-inflammatory effects.<ref name=":20" /><ref name=":21" /><ref name=":24" />

''PGLYRP2''-deficient mice also show higher [[Social behavior|sociability]] and decreased levels of [[anxiety]]-like behaviors compared with wild type mice, which indicate that PGLYRP2 affects behavior in mice.<ref name=":14" /><ref>{{Cite journal|last=Arentsen|first=Tim|last2=Khalid|first2=Roksana|last3=Qian|first3=Yu|last4=Diaz Heijtz|first4=Rochellys|date=2018-01|title=Sex-dependent alterations in motor and anxiety-like behavior of aged bacterial peptidoglycan sensing molecule 2 knockout mice|url=https://pubmed.ncbi.nlm.nih.gov/28951252|journal=Brain, Behavior, and Immunity|volume=67|pages=345–354|doi=10.1016/j.bbi.2017.09.014|issn=1090-2139|pmid=28951252}}</ref>

== Medical relevance ==
Genetic ''PGLYRP2'' variants or changed expression of PGLYRP2 are associated with some diseases. Patients with [[inflammatory bowel disease]] (IBD), which includes [[Crohn's disease|Crohn’s disease]] and [[ulcerative colitis]], have significantly more frequent missense variants in ''PGLYRP2'' gene (and also in the other three ''PGLYRP'' genes) than healthy controls.<ref name=":19" /> These results suggest that PGLYRP2 protects humans from these inflammatory diseases, and that mutations in ''PGLYRP2'' gene are among the genetic factors predisposing to these diseases. ''PGLYRP2'' variants are also associated with [[Esophageal cancer|esophageal squamous cell carcinoma]]<ref>{{Cite journal|last=Ng|first=David|last2=Hu|first2=Nan|last3=Hu|first3=Ying|last4=Wang|first4=Chaoyu|last5=Giffen|first5=Carol|last6=Tang|first6=Ze-Zhong|last7=Han|first7=Xiao-You|last8=Yang|first8=Howard H.|last9=Lee|first9=Maxwell P.|last10=Goldstein|first10=Alisa M.|last11=Taylor|first11=Philip R.|date=2008-10-01|title=Replication of a genome-wide case-control study of esophageal squamous cell carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/18649358|journal=International Journal of Cancer|volume=123|issue=7|pages=1610–1615|doi=10.1002/ijc.23682|issn=1097-0215|pmc=2552411|pmid=18649358}}</ref> and [[Parkinson's disease|Parkinson’s disease]].<ref>{{Cite journal|last=Goldman|first=Samuel M.|last2=Kamel|first2=Freya|last3=Ross|first3=G. Webster|last4=Jewell|first4=Sarah A.|last5=Marras|first5=Connie|last6=Hoppin|first6=Jane A.|last7=Umbach|first7=David M.|last8=Bhudhikanok|first8=Grace S.|last9=Meng|first9=Cheryl|last10=Korell|first10=Monica|last11=Comyns|first11=Kathleen|date=2014-08|title=Peptidoglycan recognition protein genes and risk of Parkinson's disease|url=https://pubmed.ncbi.nlm.nih.gov/24838182|journal=Movement Disorders: Official Journal of the Movement Disorder Society|volume=29|issue=9|pages=1171–1180|doi=10.1002/mds.25895|issn=1531-8257|pmc=4777298|pmid=24838182}}</ref>

Decreased expression of PGLYRP2 is associated with [[HIV]]-associated [[tuberculosis]],<ref>{{Cite journal|last=Achkar|first=Jacqueline M.|last2=Cortes|first2=Laetitia|last3=Croteau|first3=Pascal|last4=Yanofsky|first4=Corey|last5=Mentinova|first5=Marija|last6=Rajotte|first6=Isabelle|last7=Schirm|first7=Michael|last8=Zhou|first8=Yiyong|last9=Junqueira-Kipnis|first9=Ana Paula|last10=Kasprowicz|first10=Victoria O.|last11=Larsen|first11=Michelle|date=2015-09|title=Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co-infected Individuals|url=https://pubmed.ncbi.nlm.nih.gov/26501113|journal=EBioMedicine|volume=2|issue=9|pages=1160–1168|doi=10.1016/j.ebiom.2015.07.039|issn=2352-3964|pmc=4588417|pmid=26501113}}</ref> [[Lyme disease]],<ref>{{Cite journal|last=Zhou|first=Yong|last2=Qin|first2=Shizhen|last3=Sun|first3=Mingjuan|last4=Tang|first4=Li|last5=Yan|first5=Xiaowei|last6=Kim|first6=Taek-Kyun|last7=Caballero|first7=Juan|last8=Glusman|first8=Gustavo|last9=Brunkow|first9=Mary E.|last10=Soloski|first10=Mark J.|last11=Rebman|first11=Alison W.|date=01 03, 2020|title=Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease|url=https://pubmed.ncbi.nlm.nih.gov/31618575|journal=Journal of Proteome Research|volume=19|issue=1|pages=346–359|doi=10.1021/acs.jproteome.9b00569|issn=1535-3907|pmid=31618575}}</ref> [[hepatocellular carcinoma]],<ref>{{Cite journal|last=Yang|first=Zongyi|last2=Feng|first2=Jia|last3=Xiao|first3=Li|last4=Chen|first4=Xi|last5=Yao|first5=Yuanfei|last6=Li|first6=Yiqun|last7=Tang|first7=Yu|last8=Zhang|first8=Shuai|last9=Lu|first9=Min|last10=Qian|first10=Yu|last11=Wu|first11=Hongjin|date=2020-05|title=Tumor-Derived Peptidoglycan Recognition Protein 2 Predicts Survival and Antitumor Immune Responses in Hepatocellular Carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/31479523|journal=Hepatology (Baltimore, Md.)|volume=71|issue=5|pages=1626–1642|doi=10.1002/hep.30924|issn=1527-3350|pmc=7318564|pmid=31479523}}</ref> and [[myocardial infarction]].<ref>{{Cite journal|last=Das|first=Apabrita Ayan|last2=Choudhury|first2=Kamalika Roy|last3=Jagadeeshaprasad|first3=M. G.|last4=Kulkarni|first4=Mahesh J.|last5=Mondal|first5=Prakash Chandra|last6=Bandyopadhyay|first6=Arun|date=2020-06-30|title=Proteomic analysis detects deregulated reverse cholesterol transport in human subjects with ST-segment elevation myocardial infarction|url=https://pubmed.ncbi.nlm.nih.gov/32376501|journal=Journal of Proteomics|volume=222|pages=103796|doi=10.1016/j.jprot.2020.103796|issn=1876-7737|pmid=32376501}}</ref>

⚫
== See also ==

* [[Peptidoglycan recognition protein]]
* [[Peptidoglycan recognition protein 1]]
* Peptidoglycan recognition protein 3
* Peptidoglycan recognition protein 4
* [[Peptidoglycan]]
* [[Peptidoglycan]]
* [[Innate immune system]]
* [[Innate immune system]]
* [[Cell wall#Bacterial cell walls|Bacterial cell walls]]
* [[Cell wall#Bacterial%20cell%20walls|Bacterial cell walls]]


==References==
==References==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
Dziarski R, Royet J, Gupta D. Peptidoglycan Recognition Proteins and Lysozyme.  In: Encyclopedia of Immunobiology, 2016. vol. 2, pp. 389-403, Ratcliffe MJH (ed), Elsevier Ltd., ISBN-13: 978-0123742797. <nowiki>http://dx.doi.org/10.1016/B978-0-12-374279-7.02022-1</nowiki>
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Royet J, Gupta D, Dziarski R. Peptidoglycan recognition proteins: modulators of the microbiome and inflammation. Nat Rev Immunol. 2011 Nov 11;11(12):837-51. doi: 10.1038/nri3089. PMID: 22076558
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*{{cite journal |vauthors=Xu XR, Huang J, Xu ZG, etal |title=Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue= 26 |pages= 15089–94 |year= 2002 |pmid= 11752456 |doi= 10.1073/pnas.241522398 | pmc=64988 }}
Royet J, Dziarski R. Peptidoglycan Recognition Proteins: pleiotropic sensors and effectors of antimicrobial defenses.  Nat Rev Microbiol. 2007 Apr;5(4):264-77. doi: 10.1038/nrmicro1620. PMID: 17363965
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*{{cite journal | vauthors=Xu M, Wang Z, Locksley RM |title=Innate immune responses in peptidoglycan recognition protein L-deficient mice. |journal=Mol. Cell. Biol. |volume=24 |issue= 18 |pages= 7949–57 |year= 2004 |pmid= 15340057 |doi= 10.1128/MCB.24.18.7949-7957.2004 | pmc=515053 }}
Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol. 2018 Apr;18(4):243-254. doi: 10.1038/nri.2017.136. Epub 2018 Jan 2. PMID: 29292393
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*{{cite journal |vauthors=Zhang Y, van der Fits L, Voerman JS, etal |title=Identification of serum N-acetylmuramoyl-l-alanine amidase as liver peptidoglycan recognition protein 2. |journal=Biochim. Biophys. Acta |volume=1752 |issue= 1 |pages= 34–46 |year= 2005 |pmid= 16054449 |doi= 10.1016/j.bbapap.2005.07.001 }}
Laman JD, 't Hart BA, Power C, Dziarski R. Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation. Trends Mol Med. 2020 Jul;26(7):670-682. doi: 10.1016/j.molmed.2019.11.006. Epub 2020 Feb 21. PMID: 32589935
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{{refend}}


Gonzalez-Santana A, Diaz Heijtz R. Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior. Trends Mol Med. 2020 Aug;26(8):729-743. doi: 10.1016/j.molmed.2020.05.003. Epub 2020 Jun 5. PMID: 32507655
[[Category:Peptidoglycan recognition proteins]]
[[Category:Peptidoglycan recognition proteins]]


Revision as of 19:17, 2 November 2020

Peptidoglycan recognition protein 2 (PGLYRP2) is an enzyme (EC 3.5.1.28), N-acetylmuramoyl-L-alanine amidase (NAMLAA), that hydrolyzes bacterial cell wall peptidoglycan and is encoded by the PGLYRP2 gene.[1][2][3][4][5]

PGLYRP2
Identifiers
AliasesPGLYRP2, HMFT0141, PGLYRPL, PGRP-L, PGRPL, TAGL-like, tagL, tagL-alpha, tagl-beta, peptidoglycan recognition protein 2
External IDsOMIM: 608199; MGI: 1928099; HomoloGene: 49671; GeneCards: PGLYRP2; OMA:PGLYRP2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

114770

57757

Ensembl

ENSG00000161031

ENSMUSG00000079563

UniProt

Q96PD5

Q8VCS0

RefSeq (mRNA)

NM_052890
NM_001363546

NM_001271476
NM_001271477
NM_001271478
NM_001271479
NM_021319

RefSeq (protein)

NP_443122
NP_001350475

NP_001258405
NP_001258406
NP_001258407
NP_001258408
NP_067294

Location (UCSC)Chr 19: 15.47 – 15.5 MbChr 17: 32.63 – 32.64 Mb
PubMed search[8][9]
Wikidata
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Discovery

The N-acetylmuramoyl-L-alanine amidase enzymatic activity was first observed in human and mouse serum in 1981 by Branko Ladešić and coworkers.[10] The enzyme (abbreviated NAMLAA) was then purified from human serum by this[11] and other groups.[12][13][14][15] The sequence of 15 N-terminal amino acids of NAMLAA was identified,[14] but the cDNA for the protein was not cloned and the gene encoding NAMLAA was not known.

In 2000, Dan Hultmark and coworkers discovered a family of 12 Peptidoglycan Recognition Protein (PGRP) genes in Drosophila melanogaster and by homology searches of available human and mouse sequences predicted the presence of long forms of human and mouse PGRPs, which they named PGRP-L by analogy to long forms of insect PGRPs.[16]

In 2001, Roman Dziarski and coworkers discovered and cloned three human PGRPs, named PGRP-L, PGRP-Iα, and PGRP-Iβ (for long and intermediate size transcripts),[1] and established that human genome codes for a family of 4 PGRPs: PGRP-S (short PGRP)[17] and PGRP-L, PGRP-Iα, and PGRP-Iβ.[1] Subsequently, the Human Genome Organization Gene Nomenclature Committee changed the gene symbols of PGRP-S, PGRP-L, PGRP-Iα, and PGRP-Iβ to PGLYRP1 (peptidoglycan recognition protein 1), PGLYRP2 (peptidoglycan recognition protein 2), PGLYRP3 (peptidoglycan recognition protein 3), and PGLYRP4 (peptidoglycan recognition protein 4), respectively, and this nomenclature is currently also used for other mammalian PGRPs. Sergei Kiselev and coworkers also independently cloned mouse PGLYRP2 (which they named TagL).[2][18]

In 2003 Håkan Steiner and coworkers[3] and Roman Dziarski and coworkers[4] discovered that mouse[3] and human[4] PGLYRP2 (PGRP-L) proteins encoded by the mouse and human PGLYRP2 genes are N-acetylmuramoyl-L-alanine amidases. Recombinant and native human PGLYRP2 proteins were then further shown to be identical with the previously identified and purified serum NAMLAA.[19]

Tissue distribution and secretion

Human and mouse PGLYRP2 is constitutively expressed in the adult and fetal liver, from where it is secreted into the blood.[1][3][19][20][21] PGLYRP2 (NAMLAA) is present in human plasma at 100 to 200 µg/ml[15][22] and at lower concentrations in saliva, milk, cerebrospinal fluid, and synovial fluid.[22] PGLYRP2 is also expressed to a much lower level in the colon, lymph nodes, spleen, thymus, heart, and polymorphonuclear leukocyte granules.[1][23][24] PGLYRP2 is differentially expressed in the developing brain and this expression is influenced by the intestinal microbiome.[25] Bacteria and cytokines induce low level of PGLYRP2 expression in the skin and gastrointestinal and oral epithelial cells,[21][26][27][28][29] and also in intestinal intraepithelial T lymphocytes, dendritic cells, NK (natural killer) cells, and inflammatory macrophages.[30][31] Some mammals, e.g. pigs, express multiple splice forms of PGLYRP2 with differential expression.[32]

Bacteria and cytokines induce expression of PGLYRP2 in epithelial cells through the p38 mitogen activated protein kinase (MAPK) and IRAK1 (interleukin-1 receptor-associated kinase 1) signaling pathways.[26][29] Constitutive and induced expression of PGLYRP2 is controlled by different transcription factors whose binding sequences are located in different regions of the PGLYRP2 promoter.[21] Constitutive expression of PGLYRP2 in hepatocytes is regulated by transcription factors c-Jun and ATF2 (activating transcription factor 2) through sequences in the proximal region of the promoter.[21] Induced expression of PGLYRP2 in keratinocytes is regulated by transcription factors NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Sp1 (specificity protein 1) through sequences in the distal region of the promoter.[21]

Structure

PGLYRP2 has one canonical carboxy-terminal catalytic peptidoglycan-binding type 2 amidase domain (also known as a PGRP domain) with predicted peptidoglycan-binding and catalytic cleft with walls formed by α-helices and the floor by a β-sheet.[1][3][33] PGLYRP2 also has a long N-terminal segment that comprises two thirds of the PGLYRP2 sequence, has two hydrophobic regions, is not found in other mammalian PGLYRP1, PGLYRP3, and PGLYRP4 and in invertebrate PGRPs, and is unique with no identifiable functional motifs or domains.[1][3][33] The C-terminal segment is also longer than in other mammalian PGLYRPs.[1][3][33] PGLYRP2 has two pairs of cysteines in the PGRP domain that are conserved in all human PGRPs and are predicted to form two disulfide bonds.[1] Human PGLYRP2 is glycosylated[12][14] and secreted,[11][12][13][14][15][19][20] and forms non-disulfide-linked homodimers.[14]

PGLYRP2, similar to all other amidase-active PGRPs (invertebrate and vertebrate) has a conserved Zn2+-binding site in the peptidoglycan-binding cleft, which is also present in bacteriophage type 2 amidases and consists of two histidines, one tyrosine, and one cysteine (His411, Tyr447, His522, Cys530 in human PGLYRP2).[4]

Functions

The PGLYRP2 protein plays an important role in the innate immune responses.

Peptidoglycan binding and hydrolysis

PGLYRP2 is an enzyme (EC 3.5.1.28), N-acetylmuramoyl-L-alanine amidase, that binds and hydrolyzes bacterial cell wall peptidoglycan.[1][3][4][10][11][12][13][14][15] Peptidoglycan is the main component of bacterial cell wall and is a polymer of β(1-4)-linked N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) with MurNAc-attached short peptides, typically composed of alternating L and D amino acids, that cross-link the adjacent polysaccharide chains.

PGLYRP2 hydrolyzes the amide bond between the MurNAc and L-Ala, the first amino acid in the stem peptide.[3][4][10][11] This hydrolysis separates the crosslinking peptides from the polysaccharide chains and solubilizes cross-linked bacterial peptidoglycan into uncross-linked polysaccharide chains.[4] The minimal peptidoglycan fragment hydrolyzed by PGLYRP2 is MurNAc-tripeptide.[4]

The peptidoglycan-binding site, which is also the amidase catalytic domain, is located in the C-terminal PGRP domain. This PGRP domain is sufficient for the enzymatic activity of PGLYRP2, although this activity of the isolated C-terminal fragment is diminished compared with the entire PGLYRP2 molecule.[4] Zn2+ and Zn2+-binding amino acids (His411, Tyr447, and Cys530 in human PGLYRP2) are required for the amidase activity.[4] Cys419 in human PGLYRP2, which is broadly conserved in invertebrate and vertebrate PRGPs, forms a disulfide bond with Cys425 (in human PGLYRP2) and is required for the amidase activity, as this disulfide bond is essential for the structural integrity of the PGRP domain.[4] Cys530 is conserved in all amidase-active vertebrate and invertebrate PGRPs, whereas non-catalytic PGRPs (including mammalian PGLYRP1, PGLYRP3, and PGLYRP4) have serine in this position,[1] and thus the presence of Cys or Ser in this position can be used to predict amidase activity of PGRPs.[4] However, Cys530 and seven other amino acids that are all required for the amidase activity of PGRPs are not sufficient for the amidase activity, which requires additional so far unidentified amino acids.[4]

Defense against infections

PGLYRP2 plays a limited role in host defense against infections. PGLYRP2-deficient mice are more sensitive to Pseudomonas aeruginosa-induced keratitis[34] and Streptococcus pneumoniae-induced pneumonia and sepsis.[35] However, PGLYRP2-deficient mice did not show a changed susceptibility to systemic Escherichia coli, Staphylococcus aureus, and Candida albicans infections[20] or intestinal Salmonella enterica infection,[31] although the latter was accompanied by increased inflammation in the cecum.[30]

Although PGLYRP2 is not directly bacteriolytic,[4] it has antibacterial activity against both Gram-positive and Gram-negative bacteria and Chlamydia.[36]

Maintaining microbiome

Mouse PGLYRP2 plays a role in maintaining healthy microbiome, as PGLYRP2-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to colitis.[37][38]

Effects on inflammation

PGLYRP2 directly and indirectly affects inflammation and plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine, skin, joints, and brain.

Hydrolysis of peptidoglycan by PGLYRP2 diminishes peptidoglycan’s pro-inflammatory activity.[30][39] This effect is likely due to amidase activity of PGLYRP2, which separates the stem peptide from MurNAc in peptidoglycan and destroys the motif required for the peptidoglycan-induced activation of NOD2 (nucleotide-binding oligomerization domain-containing protein 2), one of the proinflammatory peptidoglycan receptors.[30]

PGLYRP2-deficient mice are more susceptible than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP2 protects mice from DSS-induced colitis.[37] Intestinal microbiome is important for this protection, because this increased sensitivity to colitis could be transferred to wild type germ-free mice by microbiome transplant from PGLYRP2-deficient mice.[37]

PGLYRP2-deficient mice are more susceptible than wild type mice to the development of experimentally induced psoriasis-like inflammation,[40] which indicates that PGLYRP2 is anti-inflammatory and protects mice from this type of skin inflammation. This pro-inflammatory effect is due to increased numbers and activity of T helper 17 (Th17) cells and decreased numbers of T regulatory (Treg) cells.[40] PGLYRP2-deficient mice are more susceptible than wild type mice to Salmonella enterica-induced intestinal inflammation,[31] which indicates that PGLYRP2 also has anti-inflammatory effect in the intestinal tract.

However, PGLYRP2 can also have opposite effects. PGLYRP2-deficient mice are more resistant than wild type mice to the development of arthritis induced by systemic administration of peptidoglycan or MurNAc-L-Ala-D-isoGln peptidoglycan fragment (muramyl dipeptide, MDP).[41] In this model, PGLYRP2 is required for the production of chemokines and cytokines that attract neutrophils to the arthritic joints.[41] PGLYRP2-deficient mice are also more resistant than wild type mice to bacterially induced keratitis[34] and inflammation in Streptococcus pneumoniae-induced lung infection.[35] These results indicate that under certain conditions PGLYRP2 has pro-inflammatory effects.[34][35][41]

PGLYRP2-deficient mice also show higher sociability and decreased levels of anxiety-like behaviors compared with wild type mice, which indicate that PGLYRP2 affects behavior in mice.[25][42]

Medical relevance

Genetic PGLYRP2 variants or changed expression of PGLYRP2 are associated with some diseases. Patients with inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, have significantly more frequent missense variants in PGLYRP2 gene (and also in the other three PGLYRP genes) than healthy controls.[33] These results suggest that PGLYRP2 protects humans from these inflammatory diseases, and that mutations in PGLYRP2 gene are among the genetic factors predisposing to these diseases. PGLYRP2 variants are also associated with esophageal squamous cell carcinoma[43] and Parkinson’s disease.[44]

Decreased expression of PGLYRP2 is associated with HIV-associated tuberculosis,[45] Lyme disease,[46] hepatocellular carcinoma,[47] and myocardial infarction.[48]

See also

References

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Further reading

Dziarski R, Royet J, Gupta D. Peptidoglycan Recognition Proteins and Lysozyme.  In: Encyclopedia of Immunobiology, 2016. vol. 2, pp. 389-403, Ratcliffe MJH (ed), Elsevier Ltd., ISBN-13: 978-0123742797. http://dx.doi.org/10.1016/B978-0-12-374279-7.02022-1

Royet J, Gupta D, Dziarski R. Peptidoglycan recognition proteins: modulators of the microbiome and inflammation. Nat Rev Immunol. 2011 Nov 11;11(12):837-51. doi: 10.1038/nri3089. PMID: 22076558

Royet J, Dziarski R. Peptidoglycan Recognition Proteins: pleiotropic sensors and effectors of antimicrobial defenses.  Nat Rev Microbiol. 2007 Apr;5(4):264-77. doi: 10.1038/nrmicro1620. PMID: 17363965

Dziarski R, Gupta D. The peptidoglycan recognition proteins (PGRPs). Genome Biol. 2006;7(8):232. doi: 10.1186/gb-2006-7-8-232. PMID: 16930467

Bastos PAD, Wheeler R, Boneca IG. Uptake, recognition and responses to peptidoglycan in the mammalian host. FEMS Microbiol Rev. 2020 Sep 8:fuaa044. doi: 10.1093/femsre/fuaa044. Online ahead of print. PMID: 32897324

Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol. 2018 Apr;18(4):243-254. doi: 10.1038/nri.2017.136. Epub 2018 Jan 2. PMID: 29292393

Laman JD, 't Hart BA, Power C, Dziarski R. Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation. Trends Mol Med. 2020 Jul;26(7):670-682. doi: 10.1016/j.molmed.2019.11.006. Epub 2020 Feb 21. PMID: 32589935

Gonzalez-Santana A, Diaz Heijtz R. Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior. Trends Mol Med. 2020 Aug;26(8):729-743. doi: 10.1016/j.molmed.2020.05.003. Epub 2020 Jun 5. PMID: 32507655

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