Fig 2: IL-17RC glycosylation is required for trafficking to the plasma membrane.a, Immunoblotting analysis of lysates of ST2 cells transduced with expression vectors coding for SF-IL-17RC harboring indicated mutations of the putative glycosylation sites. b, Flow cytometry analysis of IL-17RC surface expression in cells expressing indicated SF-IL-17RC constructs. c, Immunoblotting analysis of samples isolated through Flag IP from lysates of ST2 cells expressing indicated SF-IL-17RC constructs. d–i, Immunoblotting (d,g), flow cytometry of surface IL-17RC (e,h), and fluorescence microscopy (f,i) in Cmtm4-/- ST2 cells expressing IL-17RC-EGFP only (d,e,f) or together with CMTM4-mCherry (g,h,i). Scale bar, 5 µm. Data are representative of three (a–c,f,i) or two (d,g) independent experiments. Flow cytometry data show mean + s.e.m. from three (b) or five (e,h) independent experiments. Two-tailed Mann–Whitney test (e,h) or two-tailed unpaired t-test (b).Source data

Fig 3: CMTM4 is specifically associated with IL-17RC.a, b, Flow cytometry analysis of ST2 cells incubated with the indicated concentration of SF-IL-17A. Ligand binding was detected by Flag-APC antibody (a). Relative SF-IL-17A binding to ST2 cells was calculated from three independent experiments, mean ± s.e.m. (b). c, Immunoblotting analysis of lysates of wild-type ST2 cells that were stimulated with indicated concentrations of SF-IL-17A or commercial IL-17A (R&D Systems) for 15 min. d, Immunoblotting analysis of samples isolated through Flag immunoprecipitation from lysates of ST2 cells expressing SF-IL-17RB, SF-IL-17RD, or SF-IL-17RE. e, Comparison between murine and human IL-17RA and IL-17RC transmembrane domains. f, Flow cytometry analysis of surface expression of SF-IL-17RCWT and SF-IL-17RCTmRA ectopically expressed in ST2 cells. Mean + s.e.m. from six independent experiments. Two-tailed Mann–Whitney test. n.s. not significant. MFI, median fluorescence intensity. Data are representative of three (a–d) independent experiments. Source data

Fig 4: CMTM4 regulates IL-17R-mediated inflammation and autoimmune pathology.a, Flow cytometry analysis of intraperitoneal lavage from Cmtm4+/+ (WT) or Cmtm4-/- littermate mice that were intraperitoneally injected with IL-17A (500 ng) or PBS only for 4 h. CD45+ leukocyte subsets were gated as CD11b+F4/80+ residual macrophages, F4/80-CD11b+Ly6G+ neutrophils and F4/80-Ly6G-CD11b+Ly6C+ inflammatory monocytes. n = 12 (Cmtm4+/+ control), 13 (Cmtm4+/+ + IL-17A), 10 (Cmtm4-/- control) and 11 (Cmtm4-/- + IL-17A) in three independent experiments. Mean + s.e.m. Two-tailed Mann–Whitney test. NS, not significant. b, Flow cytometry analysis of IL-17RC surface expression in differentiated keratinocytes isolated from Cmtm4+/+ or Cmtm4-/- littermate mice. Mean + s.e.m. from five independent experiments. Two-tailed Mann–Whitney test. c, Analysis of experimental psoriasis disease progression in Cmtm4+/+ or Cmtm4-/- littermate mice treated with Aldara cream containing 5% IMQ on the shaved skin of back and ears daily for 5 consecutive days and monitored daily. n = 14 mice per group in three independent experiments. Mean ± s.e.m. score for erythema, scaling, dorsal skin thickness or combined cumulative score. Two-tailed Mann–Whitney test. d, Hematoxylin and eosin staining of sections of ear skin treated with Aldara for 4 days or the opposite ear in each mouse, which was left untreated, isolated from Cmtm4+/+ or Cmtm4-/- littermate mice. Scale bar, 100 µm, n = 6 mice per group. Mean ± s.e.m., two-tailed Mann–Whitney test. e, Real-time quantitative PCR analysis of the relative expression of DefB3, S100a8 and S100a9 transcripts in the back skin isolated from Cmtm4+/+ or Cmtm4-/- littermate mice treated or not with Aldara cream for 4 consecutive days. n = 4 for control groups, and 8 for IMQ-treated groups. Mean ± s.e.m., two-tailed Mann–Whitney test.Source data

Fig 5: CMTM4 has a substantial role in propagating experimental psoriasis, but not EAE.a,b, Analysis of experimental psoriasis disease progression in Cmtm4+/+ (WT) or Cmtm4-/- littermate mice treated with Aldara cream containing 5% imiquimod (IMQ) on the shaven back and ears daily for five consecutive days and monitored daily. n = 14 mice per group in 3 independent experiments. Photograph of mice on day 4 (a) and mean ± s.e.m. for change of ear thickness, two-tailed Mann–Whitney test (b). c, Real-time quantitative PCR analysis of the relative expression of Il23, Il17a, Il17f, Il17c, and Cmtm4 transcripts in the back skin isolated from Cmtm4+/+ or Cmtm4-/- littermate mice treated or not with Aldara cream for four consecutive days. n = 4 for control groups, and 8 for IMQ-treated groups. Mean ± s.e.m., two-tailed Mann–Whitney test. d, Analysis of experimental psoriasis disease progression in wild-type mice that were transplanted with bone marrow isolated from Cmtm4+/+ or Cmtm4-/- mice. The experiment was performed as in a. Score for erythema, scaling, dorsal skin thickness, and combined cumulative score and changes in ear thickness are shown. n = 16 mice per group in 2 independent experiments analyzed. Mean ± s.e.m., two-tailed Mann–Whitney test. e, Analysis of the expression of IL-17RA, IL-17RC, CMTM4, and IL-17A mRNA in skin samples from patients with psoriasis (lesional or nonlesional samples) or healthy donors using the Genevestigator software. Each dot represents log2 of the average expression in the given sample. GEO accession numbers are GSE121212 for dataset HS-2913 and GSE54456 for dataset HS-1529. Two-tailed Mann–Whitney test. n.s., not significant. f, Clinical scores after MOG35–55-induced EAE. Mice were monitored daily in a blinded manner. n = 12 (Cmtm4+/+) or 14 (Cmtm4-/-). Mean ± s.e.m., two-way ANOVA. Source data