| IL17RD | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | IL17RD, HH18, IL-17RD, IL17RLM, SEF, interleukin 17 receptor D | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 606807 MGI: 2159727 HomoloGene: 9717 GeneCards: IL17RD | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Interleukin 17 receptor D (also known as Sef) is a protein that in humans is encoded by the IL17RD gene.[5]
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.
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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] The SEFIR domain contains a region with sequence similarity to the TIR domain, which is characteristic of Toll-like receptors (TLRs), receptors of the interleukin 1 family, and adaptor proteins involved in the signaling pathways of these receptors. The regions within SEFIR that can be found in the TIR domain include box 1 and box 2.[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]
TLR signaling
Since the SEFIR domain contains a TIR domain, the possible role of IL-17RD in TLR signaling was investigated. One study discovered that IL-17RD interacts with TIR adaptor proteins (such as MyD88, Mal, and TRIF) following TLR stimulation. Additionally, this interaction was abolished in IL-17RD which lacks the SEFIR domain. The study concluded that IL-17RD targets TLR-induced pro-inflammatory pathways and inhibits signaling upstream of NF-κB and IRF3.[14]
TNF signaling
One study reported that TNF induces IL-17RD expression, which then serves as a feedback loop inhibiting the activation of TNF-activated NF-κB.[15] Another study focusing on renal cells describes IL-17RD to associate with TNFR2, but not TNFR1, to augment NF-κB activation.[16] The contrasting results suggest different roles of IL-17RD in various tissues.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000144730 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040717 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Interleukin 17 receptor D". Retrieved 2016-04-17.
- ^ a b Tsang M, Friesel R, Kudoh T, Dawid IB (February 2002). "Identification of Sef, a novel modulator of FGF signalling". Nature Cell Biology. 4 (2): 165–169. doi:10.1038/ncb749. PMID 11802164. S2CID 36494661.
- ^ a b Fürthauer M, Lin W, Ang SL, Thisse B, Thisse C (February 2002). "Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling". Nature Cell Biology. 4 (2): 170–174. doi:10.1038/ncb750. PMID 11802165. S2CID 32656219.
- ^ Pande S, Yang X, Friesel R (January 2021). "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling". Cell Communication and Signaling. 19 (1): 6. doi:10.1186/s12964-020-00695-7. PMC 7805053. PMID 33436016.
- ^ a b Novatchkova M, Leibbrandt A, Werzowa J, Neubüser A, Eisenhaber F (May 2003). "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. PMID 12765832.
- ^ Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (February 2006). "TGFbeta 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. PMID 16473830.
- ^ Rong Z, Wang A, Li Z, Ren Y, Cheng L, Li Y, et al. (February 2009). "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. PMC 4603938. PMID 19079364.
- ^ Gaffen SL (August 2009). "Structure and signalling in the IL-17 receptor family". Nature Reviews. Immunology. 9 (8): 556–567. doi:10.1038/nri2586. PMC 2821718. PMID 19575028.
- ^ Su Y, Huang J, Zhao X, Lu H, Wang W, Yang XO, et al. (June 2019). "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. PMID 31175175. S2CID 174805358.
- ^ Mellett M, Atzei P, Bergin R, Horgan A, Floss T, Wurst W, et al. (March 2015). "Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions". Nature Communications. 6 (1): 6669. Bibcode:2015NatCo...6.6669M. doi:10.1038/ncomms7669. PMID 25808990.
- ^ Fuchs Y, Brunwasser M, Haif S, Haddad J, Shneyer B, Goldshmidt-Tran O, et al. (September 2012). "Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB". Developmental Cell. 23 (3): 611–623. doi:10.1016/j.devcel.2012.07.013. PMID 22975329.
- ^ Yang S, Wang Y, Mei K, Zhang S, Sun X, Ren F, et al. (January 2015). "Tumor necrosis factor receptor 2 (TNFR2)·interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-κB activation". The Journal of Biological Chemistry. 290 (2): 861–871. doi:10.1074/jbc.M114.586560. PMC 4294508. PMID 25378394.
Further reading
- Kovalenko D, Yang X, Nadeau RJ, Harkins LK, Friesel R (April 2003). "Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation". The Journal of Biological Chemistry. 278 (16): 14087–14091. doi:10.1074/jbc.C200606200. PMID 12604616.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
This page was last edited on 17 February 2024, at 13:56