P-bodies

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Processing bodies (P-bodies) are distinct foci within the cytoplasm of the eukaryotic cell consisting of many enzymes involved in mRNA turnover. P-bodies have been observed in somatic cells originating from vertebrates and invertebrates, plants and yeast. To date, P-bodies have been demonstrated to play fundamental roles in general mRNA decay, nonsense-mediated mRNA decay, adenylate-uridylate-rich element mediated mRNA decay, and microRNA induced mRNA silencing.[1] Not all mRNAs which enter P-bodies are degraded, as it has been demonstrated that some mRNAs can exit P-bodies and re-initiate translation.[2][3] Purification and sequencing of the mRNA from purified processing bodies showed that these mRNAs are largely translationally repressed upstream of translation initiation and are protected from 5' mRNA decay.[4]

The following activities have been demonstrated to occur in or to be associated with P-bodies:

  • decapping and degradation of unwanted mRNAs[5]
  • storing mRNA until needed for translation[4]
  • aiding in translational repression by miRNAs (related to siRNAs)

In neurons, P-bodies move by motor proteins in response to stimulation. This is likely tied to local translation in dendrites.[6]

P-bodies were first described in the scientific literature by Bashkirov et al.[7] in 1997, in which they describe "small granules… discrete, prominent foci" as the cytoplasmic location of the mouse exoribonuclease mXrn1p. It wasn’t until 2002 that a glimpse into the nature and importance of these cytoplasmic foci was published.[8][9][10] In 2002, researchers demonstrated that multiple proteins involved with mRNA degradation localize to the foci. During this time, many descriptive names were used to identify the processing bodies, including "GW-bodies" and "decapping-bodies"; however "P-bodies" was the term chosen and is now widely used and accepted in the scientific literature.[5] Recently evidence has been presented suggesting that GW-bodies and P-bodies may in fact be different cellular components.[11] The evidence being that GW182 and Ago2, both associated with miRNA gene silencing, are found exclusively in multivesicular bodies or GW-bodies and are not localized to P-bodies. Also of note, P-bodies are not equivalent to stress granules and they contain largely non-overlapping proteins.[4] The two structures support overlapping cellular functions but generally occur under different stimuli. Hoyle et al. suggests a novel site termed EGP bodies, or stress granules, may be responsible for mRNA storage as these sites lack the decapping enzyme.[12]

Associations with microRNA[edit]

microRNA mediated repression occurs in two ways, either by translational repression or stimulating mRNA decay. miRNA recruit the RISC complex to the mRNA to which they are bound. The link to P-bodies comes by the fact that many, if not most, of the proteins necessary for miRNA gene silencing are localized to P-bodies, as reviewed by Kulkarni et al. (2010).[1][13][14][15][16] These proteins include, but are not limited to, the scaffold protein GW182, Argonaute (Ago), decapping enzymes and RNA helicases. The current evidence points toward P-bodies as being scaffolding centers of miRNA function, especially due to the evidence that a knock down of GW182 disrupts P-body formation. However, there remain many unanswered questions about P-bodies and their relationship to miRNA activity. Specifically, it is unknown whether there is a context dependent (stress state versus normal) specificity to the P-body's mechanism of action. Based on the evidence that P-bodies sometimes are the site of mRNA decay and sometimes the mRNA can exit the P-bodies and re-initiate translation, the question remains of what controls this switch. Another ambiguous point to be addressed is whether the proteins that localize to P-bodies are actively functioning in the miRNA gene silencing process or whether they are merely on standby.

Protein composition of processing bodies[edit]

In 2017 a new method to purify processing bodies was published.[4] Hubstenberger et al. used fluorescence-activated particle sorting (a method based on the ideas of fluorescence-activated cell sorting) to purify processing bodies from human epithelial cells. From these purified processing bodies they were able to use mass spectrometry and RNA sequencing to determine which proteins and RNAs are found in processing bodies, respectively. This study identified 125 proteins that are significantly associated with processing bodies.[4]

Gene ID Protein References Also found in stress granules?
MOV10 MOV10 [4] yes
EDC4 EDC4 [4] yes
ZCCHC11 TUT4 [4] no
DHX9 DHX9 [4] no
RPS27A RS27A [4] no
UPF1 RENT1 [4] yes
ZCCHC3 ZCHC3 [4] no
SMARCA5 SMCA5 [4] no
TOP2A TOP2A [4] no
HSPA2 HSP72 [4] no
SPTAN1 SPTN1 [4] no
SMC1A SMC1A [4] no
ACTBL2 ACTBL [4] yes
SPTBN1 SPTB2 [4] no
DHX15 DHX15 [4] no
ARG1 ARGI1 [4] no
TOP2B TOP2B [4] no
APOBEC3F ABC3F [4] no
NOP58 NOP58 [4] yes
RPF2 RPF2 [4] no
S100A9 S10A9 [4] yes
DDX41 DDX41 [4] no
KIF23 KIF23 [4] yes
AZGP1 ZA2G [4] no
DDX50 DDX50 [4] yes
SERPINB3 SPB3 [4] no
SBSN SBSN [4] no
BAZ1B BAZ1B [4] no
MYO1C MYO1C [4] no
EIF4A3 IF4A3 [4] no
SERPINB12 SPB12 [4] no
EFTUD2 U5S1 [4] no
RBM15B RB15B [4] no
AGO2 AGO2 [4] yes
MYH10 MYH10 [4] no
DDX10 DDX10 [4] no
FABP5 FABP5 [4] no
SLC25A5 ADT2 [4] no
DMKN DMKN [4] no
DCP2 DCP2 [4][9][10][17] no
S100A8 S10A8 [4] no
NCBP1 NCBP1 [4] no
YTHDC2 YTDC2 [4] no
NOL6 NOL6 [4] no
XAB2 SYF1 [4] no
PUF60 PUF60 [4] no
RBM19 RBM19 [4] no
WDR33 WDR33 [4] no
PNRC1 PNRC1 [4] no
SLC25A6 ADT3 [4] no
MCM7 MCM7 [4] yes
GSDMA GSDMA [4] no
HSPB1 HSPB1 [4] yes
LYZ LYSC [4] no
DHX30 DHX30 [4] yes
BRIX1 BRX1 [4] no
MEX3A MEX3A [4] yes
MSI1 MSI1H [4] yes
RBM25 RBM25 [4] no
UTP11L UTP11 [4] no
UTP15 UTP15 [4] no
SMG7 SMG7 [4] no
AGO1 AGO1 [4] yes
LGALS7 LEG7 [4] no
MYO1D MYO1D [4] no
XRCC5 XRCC5 [4] no
DDX6 DDX6/p54/RCK [4][18][19] yes
ZC3HAV1 ZCCHV [4] yes
DDX27 DDX27 [4] no
NUMA1 NUMA1 [4] no
DSG1 DSG1 [4] no
NOP56 NOP56 [4] no
LSM14B LS14B [4] yes
EIF4ENIF1 4ET [4] no
LSM14A LS14A [4] yes
IGF2BP2 IF2B2 [4] yes
DDX21 DDX21 [4] yes
DSC1 DSC1 [4] no
NKRF NKRF [4] no
DCP1B DCP1B [4][19] no
SMC3 SMC3 [4] no
RPS3 RS3 [4] yes
PUM1 PUM1 [4] yes
PIP PIP [4] no
RPL26 RL26 [4] no
GTPBP4 NOG1 [4] no
PES1 PESC [4] no
DCP1A DCP1A [4][9][10][17][20] yes
ELAVL2 ELAV2 [4] yes
IGLC2 LAC2 [4] no
IGF2BP1 IF2B1 [4] yes
RPS16 RS16 [4] no
HNRNPU HNRPU [4] no
IGF2BP3 IF2B3 [4] yes
SF3B1 SF3B1 [4] no
STAU2 STAU2 [4] yes
ZFR ZFR [4] no
HNRNPM HNRPM [4] no
ELAVL1 ELAV1 [4] yes
FAM120A F120A [4] yes
STRBP STRBP [4] no
RBM15 RBM15 [4] no
LMNB2 LMNB2 [4] no
NIFK MK67I [4] no
TF TRFE [4] no
HNRNPR HNRPR [4] no
LMNB1 LMNB1 [4] no
ILF2 ILF2 [4] no
H2AFY H2AY [4] no
RBM28 RBM28 [4] no
MATR3 MATR3 [4] no
SYNCRIP HNRPQ [4] yes
HNRNPCL1 HNRCL [4] no
APOA1 APOA1 [4] no
XRCC6 XRCC6 [4] no
RPS4X RS4X [4] no
DDX18 DDX18 [4] no
ILF3 ILF3 [4] yes
SAFB2 SAFB2 [4] yes
RBMX RBMX [4] no
ATAD3A ATD3A [4] yes
HNRNPC HNRPC [4] no
RBMXL1 RMXL1 [4] no
IMMT IMMT [4] no
ALB ALBU [4] no
CSNK1D CK1𝛿 [18] no
XRN1 XRN1 [7][9][17] yes
TNRC6A GW182 [17][21][20][22] no
LSM4 LSM4 [20][9] no
LSM1 LSM1 [9] no
LSM2 LSM2 [9] no
LSM3 LSM3 [9][19] yes
LSM5 LSM5 [9] no
LSM6 LSM6 [9] no
LSM7 LSM7 [9] no
CNOT1 CCR4/CNOT1 [19] yes

References[edit]

  1. ^ a b Kulkarni, M.; Ozgur, S.; Stoecklin, G. (2010). "On track with P-bodies". Biochemical Society Transactions. 38 (Pt 1): 242–251. doi:10.1042/BST0380242. PMID 20074068. 
  2. ^ Brengues, M.; Teixeira, D.; Parker, R. (2005). "Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies". Science. 310 (5747): 486–489. Bibcode:2005Sci...310..486B. doi:10.1126/science.1115791. PMC 1863069Freely accessible. PMID 16141371. 
  3. ^ Bhattacharyya, S.; Habermacher, R.; Martine, U.; Closs, E.; Filipowicz, W. (2006). "Relief of microRNA-mediated translational repression in human cells subjected to stress". Cell. 125 (6): 1111–1124. doi:10.1016/j.cell.2006.04.031. PMID 16777601. 
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce cf cg ch ci cj ck cl cm cn co cp cq cr cs ct cu cv cw cx cy cz da db dc dd de df dg dh di dj dk dl dm dn do dp dq dr ds dt du dv dw dx dy dz Hubstenberger, Arnaud; Courel, Maïté; Bénard, Marianne; Souquere, Sylvie; Ernoult-Lange, Michèle; Chouaib, Racha; Yi, Zhou; Morlot, Jean-Baptiste; Munier, Annie (2017-09-27). "P-Body Purification Reveals the Condensation of Repressed mRNA Regulons". Molecular Cell. doi:10.1016/j.molcel.2017.09.003. ISSN 1097-4164. PMID 28965817. 
  5. ^ a b Sheth, Ujwal; Parker, Roy (2003-05-02). "Decapping and decay of messenger RNA occur in cytoplasmic processing bodies". Science. 300 (5620): 805–808. doi:10.1126/science.1082320. ISSN 1095-9203. PMC 1876714Freely accessible. PMID 12730603. 
  6. ^ Cougot, Nicolas; Bhattacharyya, Suvendra N.; Tapia-arancibia, Lucie; Bordonne, Remy; Filipowicz, Witold; Bertrand, Edouard; Rage, Florence (2008). "Dendrites of Mammalian Neurons Contain Specialized P-Body-Like Structures That Respond to Neuronal Activation". Journal of Neuroscience. 28 (51): 13793–804. doi:10.1523/JNEUROSCI.4155-08.2008. PMID 19091970. 
  7. ^ a b Bashkirov, V. I.; Scherthan, H.; Solinger, J. A.; Buerstedde, J. -M.; Heyer, W. -D. (1997). "A Mouse Cytoplasmic Exoribonuclease (mXRN1p) with Preference for G4 Tetraplex Substrates". Journal of Cell Biology. 136 (4): 761–73. doi:10.1083/jcb.136.4.761. PMC 2132493Freely accessible. PMID 9049243. 
  8. ^ Eystathioy, T.; Chan, E.; Tenenbaum, S.; Keene, J.; Griffith, K.; Fritzler, M. (2002). "A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles". Molecular Biology of the Cell. 13 (4): 1338–1351. doi:10.1091/mbc.01-11-0544. PMC 102273Freely accessible. PMID 11950943. 
  9. ^ a b c d e f g h i j k Ingelfinger, D.; Arndt-Jovin, D. J.; Lührmann, R.; Achsel, T. (2002). "The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci". RNA. 8 (12): 1489–1501. doi:10.1017/S1355838202021726. PMC 1370355Freely accessible. PMID 12515382. 
  10. ^ a b c Van Dijk, E.; Cougot, N.; Meyer, S.; Babajko, S.; Wahle, E.; Séraphin, B. (2002). "Human Dcp2: A catalytically active mRNA decapping enzyme located in specific cytoplasmic structures". The EMBO Journal. 21 (24): 6915–6924. doi:10.1093/emboj/cdf678. PMC 139098Freely accessible. PMID 12486012. 
  11. ^ Gibbings, D.; Ciaudo, C.; Erhardt, M.; Voinnet, O. (2009). "Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity". Nature Cell Biology. 11 (9): 1143–1149. doi:10.1038/ncb1929. PMID 19684575. 
  12. ^ Hoyle, N.; Castelli, L.; Campbell, S.; Holmes, L.; Ashe, M. (2007). "Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies". Journal of Cell Biology. 179 (1): 65–74. doi:10.1083/jcb.200707010. PMC 2064737Freely accessible. PMID 17908917. 
  13. ^ Liu, J.; Valencia-Sanchez, M.; Hannon, G.; Parker, R. (2005). "MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies". Nature Cell Biology. 7 (7): 719–723. doi:10.1038/ncb1274. PMC 1855297Freely accessible. PMID 15937477. 
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  16. ^ Eystathioy, T.; Jakymiw, A.; Chan, E. K.; Séraphin, B.; Cougot, N.; Fritzler, M. J. (2003). "The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies". RNA. 9 (10): 1171–1173. doi:10.1261/rna.5810203. PMC 1370480Freely accessible. PMID 13130130. 
  17. ^ a b c d Kedersha, Nancy; Stoecklin, Georg; Ayodele, Maranatha; Yacono, Patrick; Lykke-Andersen, Jens; Fritzler, Marvin J.; Scheuner, Donalyn; Kaufman, Randal J.; Golan, David E. (2005-06-20). "Stress granules and processing bodies are dynamically linked sites of mRNP remodeling". The Journal of Cell Biology. 169 (6): 871–884. doi:10.1083/jcb.200502088. ISSN 0021-9525. PMC 2171635Freely accessible. PMID 15967811. 
  18. ^ a b Zhang, Bo; Shi, Qian; Varia, Sapna N.; Xing, Siyuan; Klett, Bethany M.; Cook, Laura A.; Herman, Paul K. (July 2016). "The Activity-Dependent Regulation of Protein Kinase Stability by the Localization to P-Bodies". Genetics. 203 (3): 1191–1202. doi:10.1534/genetics.116.187419. ISSN 1943-2631. PMC 4937477Freely accessible. PMID 27182950. 
  19. ^ a b c d Cougot, Nicolas; Babajko, Sylvie; Séraphin, Bertrand (April 2004). "Cytoplasmic foci are sites of mRNA decay in human cells". The Journal of Cell Biology. 165 (1): 31–40. doi:10.1083/jcb.200309008. ISSN 0021-9525. PMC 2172085Freely accessible. PMID 15067023. 
  20. ^ a b c Eystathioy, Theophany; Jakymiw, Andrew; Chan, Edward K. L.; Séraphin, Bertrand; Cougot, Nicolas; Fritzler, Marvin J. (October 2003). "The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies". RNA. 9 (10): 1171–1173. doi:10.1261/rna.5810203. ISSN 1355-8382. PMC 1370480Freely accessible. PMID 13130130. 
  21. ^ Eystathioy, Theophany; Chan, Edward K. L.; Tenenbaum, Scott A.; Keene, Jack D.; Griffith, Kevin; Fritzler, Marvin J. (April 2002). "A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles". Molecular Biology of the Cell. 13 (4): 1338–1351. doi:10.1091/mbc.01-11-0544. ISSN 1059-1524. PMID 11950943. 
  22. ^ Yang, Zheng; Jakymiw, Andrew; Wood, Malcolm R.; Eystathioy, Theophany; Rubin, Robert L.; Fritzler, Marvin J.; Chan, Edward K. L. (2004-11-01). "GW182 is critical for the stability of GW bodies expressed during the cell cycle and cell proliferation". Journal of Cell Science. 117 (Pt 23): 5567–5578. doi:10.1242/jcs.01477. ISSN 0021-9533. PMID 15494374. 

Further reading[edit]

  • Kulkarni et al. provide a review of P-bodies and a table of all proteins detected in the P-bodies as of 2010. Kulkarni, M.; Ozgur, S.; Stoecklin, G. (2010). "On track with P-bodies". Biochemical Society Transactions. 38 (Pt 1): 242–251. doi:10.1042/BST0380242. PMID 20074068. 
  • Eulalio, Ana; Behm-Ansmant, Isabelle; Izaurralde, Elisa (January 2007). "P bodies: at the crossroads of post-transcriptional pathways". Nat Rev Mol Cell Biol. 8 (1): 9–22. doi:10.1038/nrm2080. PMID 17183357. 
  • Marx, J. (2005). "MOLECULAR BIOLOGY: P-Bodies Mark the Spot for Controlling Protein Production". Science. 310 (5749): 764–765. doi:10.1126/science.310.5749.764. PMID 16272094. 
  • Anderson, P.; Kedersha, N. (2009). "RNA granules: post-transcriptional and epigenetic modulators of gene expression". Nature Reviews. Molecular Cell Biology. 10 (6): 430–436. doi:10.1038/nrm2694. PMID 19461665.