Biology: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]

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.[2][3]

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.[4] 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.[5]

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.[2] 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.[3] 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.[5] 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).[6] 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.[7] However, full-body IL-17RD knockout mice do not present with any apparent phenotype.[8] 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.[9]

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.[10]

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.[11] Another study focusing on renal cells describes IL-17RD to associate with TNFR2, but not TNFR1, to augment NF-κB activation.[12] The contrasting results suggest different roles of IL-17RD in various tissues.

References

  1. ↑ "Entrez Gene: Interleukin 17 receptor D". https://www.ncbi.nlm.nih.gov/gene/54756. 
  2. ↑ 2.0 2.1 "Identification of Sef, a novel modulator of FGF signalling". Nature Cell Biology 4 (2): 165–169. February 2002. doi:10.1038/ncb749. PMID 11802164. 
  3. ↑ 3.0 3.1 "Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling". Nature Cell Biology 4 (2): 170–174. February 2002. doi:10.1038/ncb750. PMID 11802165. 
  4. ↑ "Interleukin-17 receptor D (Sef) is a multi-functional regulator of cell signaling". Cell Communication and Signaling 19 (1): 6. January 2021. doi:10.1186/s12964-020-00695-7. PMID 33436016. 
  5. ↑ 5.0 5.1 "The STIR-domain superfamily in signal transduction, development and immunity". Trends in Biochemical Sciences 28 (5): 226–229. May 2003. doi:10.1016/S0968-0004(03)00067-7. PMID 12765832. 
  6. ↑ "TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells". Immunity 24 (2): 179–189. February 2006. doi:10.1016/j.immuni.2006.01.001. PMID 16473830. 
  7. ↑ "IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling". Cell Research 19 (2): 208–215. February 2009. doi:10.1038/cr.2008.320. PMID 19079364. 
  8. ↑ "Structure and signalling in the IL-17 receptor family". Nature Reviews. Immunology 9 (8): 556–567. August 2009. doi:10.1038/nri2586. PMID 19575028. 
  9. ↑ "Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation". Science Immunology 4 (36). June 2019. doi:10.1126/sciimmunol.aau9657. PMID 31175175. 
  10. ↑ "Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions". Nature Communications 6 (1): 6669. March 2015. doi:10.1038/ncomms7669. PMID 25808990. Bibcode: 2015NatCo...6.6669M. 
  11. ↑ "Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB". Developmental Cell 23 (3): 611–623. September 2012. doi:10.1016/j.devcel.2012.07.013. PMID 22975329. 
  12. ↑ "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. January 2015. doi:10.1074/jbc.M114.586560. PMID 25378394. 

Further reading

  • "Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation". The Journal of Biological Chemistry 278 (16): 14087–14091. April 2003. 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.



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