CMTM4 as a new partner for IL-17 receptor: adding a piece in the puzzle of IL17-driven diseases

IL-17 has emerged as an important cytokine in protecting the host from mucosal infections, but also as a pathogenic determinant and therapeutic target in numerous autoimmune and inflammatory diseases (e.g. psoriasis, psoriatic arthritis and ankylosing spondylitis, inflammatory bowel disease and multiple sclerosis) [(1)](#ref-0001). The IL-17 family includes six members (IL-17A to IL-17F) that act through the IL-17 receptors [(1)](#ref-0001). The most studied IL-17A, as well as IL-17F, binds to IL-17RA and IL-17RC resulting in heterodimerization. Currently IL-17A, IL-17F, IL-17RA or IL-23, a cytokine produced by innate immune cells that promotes expansion of Th17 cell populations, are targetable by monoclonal antibodies (mAbs). These mAbs have been approved for the treatment of different autoimmune diseases, most notably psoriasis, where their efficacy has outperformed conventional non-steroidal anti-inflammatory and tumor necrosis factor (TNF) blocking drugs. However, clinical trials and real-life experience have shown an increase in fungal and bacterial upper respiratory tract infections in patients treated with mAbs that block IL-23/IL-17 signaling. Accordingly, single nucleotide polymorphisms in genes encoding IL-17A, IL-17RA, IL-17RC, IL-23, or NF-κB activator 1 (ACT1, an adapter protein downstream of the IL-17R) which abrogate cellular responsiveness to IL-17A, were associated with susceptibility to chronic mucocutaneous candidiasis (CMC), a persistent infection of the skin, nails, and/or mucous membranes with commensal Candida species [(2)](#ref-0002). So new effective targeted approaches in IL-17 signaling are desirable. Knizkova and colleagues identified a new adaptor molecule involved in the IL-17/IL-17R cascade [(3)](#ref-0003). Through murine and human cell models, the authors found that CMTM4 (CKLF Like MARVEL Transmembrane Domain Containing 4) constitutively bound to the subunit IL-17RC becoming integral part of the IL-17R signaling complex (IL-17RSC) upon IL-17A stimulation. CMTM4 promoted the surface expression of IL-17RC by regulating posttranslational modifications, especially IL-17RC glycosylation and trafficking to trans-Golgi up to plasma membrane. CMTM4 was required for the recruitment of adapter ACT1, for the activation of p38, JNK and transcription of genes encoding proinflammatory cytokines upon IL-17A stimulation (Figure 1A). Keratinocytes from the tail of Cmtm4−/− mice specifically express lower levels of IL-17RC respect to Cmtm4 mice (Figure 1B). In vivo , when imiquimod (IMQ) was applied on the ears or shaven backs of Cmtm4 mice, they developed less severe psoriatic lesions and lower local expression of IL-17A target genes compared to Cmtm4 mice (Figure 1C).