Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.

Czech Centre for Phenogenomics and Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Immunity and Cell Communication BIOCEV 1st Faculty of Medicine Charles University Vestec Czech Republic

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Sci Signal. 2022 Nov 29;15(762):eadf9180. doi: 10.1126/scisignal.adf9180. PubMed

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Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat. Rev. Immunol. 2010;10:479–489. PubMed

Harrington LE, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 2005;6:1123–1132. PubMed

Park H, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 2005;6:1133–1141. PubMed PMC

Puel A, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332:65–68. PubMed PMC

Ling Y, et al. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J. Exp. Med. 2015;212:619–631. PubMed PMC

Levy R, et al. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc. Natl Acad. Sci. USA. 2016;113:E8277–E8285. PubMed PMC

Boisson B, et al. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity. 2013;39:676–686. PubMed PMC

Li X, Bechara R, Zhao J, McGeachy MJ, Gaffen SL. IL-17 receptor-based signaling and implications for disease. Nat. Immunol. 2019;20:1594–1602. PubMed PMC

Zhao J, Chen X, Herjan T, Li X. The role of interleukin-17 in tumor development and progression. J. Exp. Med. 2020;217:e20190297. PubMed PMC

Yao Z, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995;3:811–821. PubMed

Toy D, et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 2006;177:36–39. PubMed

Kuestner RE, et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J. Immunol. 2007;179:5462–5473. PubMed PMC

Hu Y, et al. IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol. 2010;184:4307–4316. PubMed

McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 family of cytokines in health and disease. Immunity. 2019;50:892–906. PubMed PMC

Draberova H, et al. Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop. EMBO J. 2020;39:e104202. PubMed PMC

Goepfert A, Lehmann S, Blank J, Kolbinger F, Rondeau JM. Structural analysis reveals that the cytokine IL-17F forms a homodimeric complex with receptor IL-17RC to drive IL-17RA-independent signaling. Immunity. 2020;52:499–512. PubMed

Schwanhausser B, et al. Global quantification of mammalian gene expression control. Nature. 2011;473:337–342. PubMed

Huang XD, Zhang H, He MX. Comparative and evolutionary analysis of the interleukin 17 gene family in invertebrates. PLoS ONE. 2015;10:e0132802. PubMed PMC

Mezzadra R, et al. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017;549:106–110. PubMed PMC

Stanley, P. Golgi glycosylation. Cold Spring Harb. Perspect. Biol.3, a005199 (2011). PubMed PMC

Helenius A, Aebi M. Intracellular functions of N-linked glycans. Science. 2001;291:2364–2369. PubMed

Wright JF, et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J. Immunol. 2008;181:2799–2805. PubMed

Chang SH, Park H, Dong C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 2006;281:35603–35607. PubMed

Qian Y, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 2007;8:247–256. PubMed

Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 2000;191:1233–1240. PubMed PMC

Qu F, et al. TRAF6-dependent Act1 phosphorylation by the IkappaB kinase-related kinases suppresses interleukin-17-induced NF-kappaB activation. Mol. Cell. Biol. 2012;32:3925–3937. PubMed PMC

Birling MC, et al. A resource of targeted mutant mouse lines for 5,061 genes. Nat. Genet. 2021;53:416–419. PubMed PMC

Witowski J, et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GRO alpha chemokine from mesothelial cells. J. Immunol. 2000;165:5814–5821. PubMed

van der Fits L, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 2009;182:5836–5845. PubMed

Moos S, Mohebiany AN, Waisman A, Kurschus FC. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. J. Invest. Dermatol. 2019;139:1110–1117. PubMed

Matsumoto, R. et al. Epithelial TRAF6 drives IL-17-mediated psoriatic inflammation. JCI Insight3, e121175 (2018). PubMed PMC

Su Y, et al. Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation. Sci. Immunol. 2019;4:eaau9657. PubMed

Li B, et al. Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms. J. Invest. Dermatol. 2014;134:1828–1838. PubMed PMC

Tsoi LC, et al. Atopic dermatitis Is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J. Invest. Dermatol. 2019;139:1480–1489. PubMed PMC

Hofstetter HH, et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol. 2005;237:123–130. PubMed

Haak S, et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 2009;119:61–69. PubMed PMC

Komiyama Y, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 2006;177:566–573. PubMed

Stanley P. What have we learned from glycosyltransferase knockouts in mice. J. Mol. Biol. 2016;428:3166–3182. PubMed PMC

El Malki K, et al. An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J. Invest. Dermatol. 2013;133:441–451. PubMed

Regen, T. et al. IL-17 controls central nervous system autoimmunity through the intestinal microbiome. Sci. Immunol.6, eaaz6563 (2021). PubMed

Dai X, et al. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol. Cell. 2021;81:2317–2331. PubMed PMC

Burr ML, et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 2017;549:101–105. PubMed PMC

Carroll MC. The complement system in regulation of adaptive immunity. Nat. Immunol. 2004;5:981–986. PubMed

Labun K, et al. CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res. 2019;47:W171–W174. PubMed PMC

Ran FA, et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 2013;8:2281–2308. PubMed PMC

Masuda T, Tomita M, Ishihama Y. Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. J. Proteome Res. 2008;7:731–740. PubMed

Rappsilber J, Mann M, Ishihama Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2007;2:1896–1906. PubMed

Cox J, et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell Proteom. 2014;13:2513–2526. PubMed PMC

Tyanova S, et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods. 2016;13:731–740. PubMed

Hruz T, et al. Genevestigator v3: a reference expression database for the meta-analysis of transcriptomes. Adv. Bioinformatics. 2008;2008:420747. PubMed PMC

He S, et al. Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs. Genome Biol. 2020;21:294. PubMed PMC

Sole-Boldo L, et al. Single-cell transcriptomes of the human skin reveal age-related loss of fibroblast priming. Commun. Biol. 2020;3:188. PubMed PMC

Stuart T, et al. Comprehensive integration of single-cell data. Cell. 2019;177:1888–1902. PubMed PMC

Lichti U, Anders J, Yuspa SH. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat. Protoc. 2008;3:799–810. PubMed PMC

Moudra A, et al. Phenotypic and clonal stability of antigen-inexperienced memory-like T cells across the genetic background, hygienic status, and aging. J. Immunol. 2021;206:2109–2121. PubMed PMC

Perez-Riverol Y, et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 2022;50:D543–D552. PubMed PMC

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