CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology

Abstract

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.

CMTM3 protects the gastric epithelial cells from apoptosis and promotes IL-8 by stabilizing NEMO during Helicobacter pylori infection

“…CMTM6 and CMTM4 reduce the ubiquitylation of PD-L1 and increase its protein half-life, which affects tumor immune responses [ 22 , 23 ]. CMTM4 is also identified as a component of IL-17R and mediates autoimmune diseases [ 24 ]. This work characterizes a new role of CMTM3 as an immunity regulator during H. pylori infection.…”

“…Some CMTM family members are immunity regulators [22][23][24]. H. pylori induces IL-8 expression in gastric epithelial cells, which is an important source of IL-8 [25].…”

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

“…Knizkova and colleagues identified a new adaptor molecule involved in the IL‐17/IL‐17R cascade 3 . 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.…”

“…volved in the IL-17/IL-17R cascade. 3 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.…”

“…In summary, the study by Knizkova and colleagues adds a new piece in the puzzle of IL-17/IL-17R pathway, since highlights CMTM4 as an essential subunit of the IL-17R, required for the IL-17R signaling. 3 Given its role in mediating IL-17A-induced responses and its specific binding to IL-17RC subunit, the targeting of CMTM4 could represent a new therapeutic opportunity to selectively inhibit IL-17RC-mediated IL-17A signaling in autoimmune diseases.…”