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IL17RD

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Interleukin 17 receptor D (also known as Sef) is a protein that in humans is encoded by the IL17RD gene.[1]

IL17RD
Identifiers
AliasesIL17RD, HH18, IL-17RD, IL17RLM, SEF, interleukin 17 receptor D
External IDsOMIM: 606807; MGI: 2159727; HomoloGene: 9717; GeneCards: IL17RD; OMA:IL17RD - orthologs
Orthologs
SpeciesHumanMouse
Entrez

54756

171463

Ensembl

ENSG00000144730

ENSMUSG00000040717

UniProt

Q8NFM7

Q8JZL1

RefSeq (mRNA)

NM_017563
NM_001318864

NM_027265
NM_134437

RefSeq (protein)

NP_001305793
NP_060033

NP_602319

Location (UCSC)Chr 3: 57.09 – 57.17 MbChr 14: 26.76 – 26.83 Mb
PubMed search[4][5]
Wikidata
View/Edit HumanView/Edit Mouse

This gene encodes a membrane protein belonging to the interleukin-17 receptor (IL-17R) protein family. Alternate splicing generates multiple transcript variants encoding distinct isoforms. IL-17RD has been described to limit fibroblast growth factor receptor (FGFR) signaling and to be a part of the IL-17 receptor signaling complex.

Identification

IL-17RD was initially discovered during a large-scale in situ hybridization screen for genes regulating zebrafish embryogenesis. It was identified as a part of a synexpression group (genes with similar spatio-temporal expression) with negative regulators of fibroblast growth factor (FGF) and termed Sef (similar expression to FGF genes). The name was later changed to IL-17RD due to its sequence similarity to other IL-17 receptors. It was further determined that IL-17RD co-immunoprecipitates with FGF receptor (FGFR) and inhibits FGF signaling at the level of signal transduction and not by interfering with the ligand or its binding to FGFR [6][7].

Structure

IL-17RD is a type I transmembrane protein containing extracellular Ig-like domain followed by a fibronectin type III domain, a short transmembrane domain of ~20 amino acids, and an intracellular SEFIR domain  which was identified in IL-17 receptors and some soluble factors involved in IL-17 signaling [8][9].

IL-17RD in development

IL-17RD (Sef) was identified as part of a group of genes involved in FGF signaling in zebrafish and Xenopus laevis embryo. Injection of 1-cell stage embryo with sef mRNA lead to ventralization of the embryo, a similar effect observed after injection with XFD (a dominant negative of FGF receptor), suggesting its function as a negative regulator of FGF receptor signaling. Co-immunoprecipitation assay revealed that the intracellular part, but not the SEFIR domain, is critical for IL-17RD association with FGFR [6]. One of the pathways activated by stimulation of FGFR is Ras/MAPK (the rest being PI3/AKT and PLCγ). Injection of embryos with high amounts of Ras, Raf or MEK causes cell cycle arrest, which can be rescued by co-injection of IL-17RD, further supporting the role of IL-17RD in negative regulation of FGFR signaling. Moreover, IL-17RD appears to regulate FGF signaling at the level of downstream signaling, not the receptor, since overexpression of FGF or FGFR does not cause cell cycle arrest [7]. Taken together IL-17RD seems to negatively regulate FGFR signaling by limiting MAPK signaling via its intracellular domain.

IL-17RD in inflammation

IL-17 signaling

The IL-17 receptor family belongs to a group of structurally similar receptors with a distinctive SEFIR (Sef and IL-17R) domain [9]. The founding member, IL-17RA, along with IL-17RC serve as a receptor complex for IL-17. IL-17 is a proinflammatory cytokine mainly produced by Th17 subset of T cells and plays an important role in extracellular pathogen elimination as well as several autoinflammatory diseases (such as psoriasis or rheumatoid arthritis) [10]. IL-17RD has been reported to associate and co-localize with IL-17RA, mediate IL-17 signaling, and interact with TRAF6 (an IL-17 downstream molecule). Moreover, deletion of IL-17RD intracellular domain has a dominant negative effect and suppresses IL-17 signaling. In contrast, deletion of extracellular domain had no effect on IL-17 signaling [11]. However, full-body IL-17RD knockout mice do not present with any apparent phenotype [12]. This might be accounted for by the presence of IL-17RC which to an extent substitutes IL-17RD. It is important to note, however, that IL-17RC or IL-17RD deletion fails to protect against imiquimod-induced psoriasis [13].

References

  1. ^ "Entrez Gene: Interleukin 17 receptor D". Retrieved 2016-04-17.
  2. ^ a b c GRCh38: Ensembl release 89: ENSG00000144730 – Ensembl, May 2017
  3. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040717 – Ensembl, May 2017
  4. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  6. ^ a b Tsang, Michael; Friesel, Robert; Kudoh, Tetsuhiro; Dawid, Igor B (2002-02). "Identification of Sef, a novel modulator of FGF signalling". Nature Cell Biology. 4 (2): 165–169. doi:10.1038/ncb749. ISSN 1465-7392. {{cite journal}}: Check date values in: |date= (help)
  7. ^ a b Fürthauer, Maximilian; Lin, Wei; Ang, Siew-Lan; Thisse, Bernard; Thisse, Christine (2002-02). "Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling". Nature Cell Biology. 4 (2): 170–174. doi:10.1038/ncb750. ISSN 1465-7392. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Pande, Shivangi; Yang, Xuehui; Friesel, Robert (2021-12). "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling". Cell Communication and Signaling. 19 (1). doi:10.1186/s12964-020-00695-7. ISSN 1478-811X. PMC 7805053. PMID 33436016. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  9. ^ a b Novatchkova, Maria; Leibbrandt, Andreas; Werzowa, Johannes; Neubüser, Annette; Eisenhaber, Frank (2003-05). "The STIR-domain superfamily in signal transduction, development and immunity". Trends in Biochemical Sciences. 28 (5): 226–229. doi:10.1016/S0968-0004(03)00067-7. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Veldhoen, Marc; Hocking, Richard J.; Atkins, Christopher J.; Locksley, Richard M.; Stockinger, Brigitta (2006-02). "TGFβ in the Context of an Inflammatory Cytokine Milieu Supports De Novo Differentiation of IL-17-Producing T Cells". Immunity. 24 (2): 179–189. doi:10.1016/j.immuni.2006.01.001. {{cite journal}}: Check date values in: |date= (help)
  11. ^ Rong, Zhili; Wang, Anan; Li, Zhiyong; Ren, Yongming; Cheng, Long; Li, Yinghua; Wang, Yinyin; Ren, Fangli; Zhang, Xiaoning; Hu, Jim; Chang, Zhijie (2009-02). "IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling". Cell Research. 19 (2): 208–215. doi:10.1038/cr.2008.320. ISSN 1001-0602. PMC 4603938. PMID 19079364. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  12. ^ Gaffen, Sarah L. (2009-08). "Structure and signalling in the IL-17 receptor family". Nature Reviews Immunology. 9 (8): 556–567. doi:10.1038/nri2586. ISSN 1474-1733. PMC 2821718. PMID 19575028. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  13. ^ Su, Yang; Huang, Jinling; Zhao, Xiaohong; Lu, Huiping; Wang, Wang; Yang, Xuexian O.; Shi, Yuling; Wang, Xiaohu; Lai, Yuping; Dong, Chen (2019-06-07). "Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation". Science Immunology. 4 (36). doi:10.1126/sciimmunol.aau9657. ISSN 2470-9468.

Further reading


This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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