TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis.
TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis.
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作者：
Chen M;Amado N;Tan J;Reis A;Ge M;Abreu JG;He X
通过卷曲（FZD）蛇形受体家族的Wnt信号传导对于胚胎发生和体内平衡是必不可少的，并且FZD蛋白水平的严格控制对于干细胞调节是至关重要的。通过在人类细胞中进行CRISPR/Cas9全基因组筛选，我们鉴定了TMEM 79/MATTRIN，一种孤儿多跨膜蛋白，作为Wnt/FZD信号传导的特异性抑制剂。TMEM 79在生物发生期间与FZD相互作用，并促进FZD降解，而不依赖于ZNRF 3/RNF 43泛素连接酶（R-spondin受体）。TMEM 79与泛素特异性蛋白酶8（USP 8）相互作用，其激活突变是人类肿瘤发生的基础。TMEM 79特异性抑制FZD的USP 8去遍在化，从而控制USP 8底物特异性并促进FZD降解。Tmem 79和Usp 8基因具有前双侧起源，并且Tmem 79抑制Usp 8和Wnt信号传导是非洲爪蟾胚胎中前神经发育和原肠胚形成所需的。TMEM 79是特应性皮炎的易感基因，表明Wnt/FZD信号转导失调是这种最常见但神秘的炎性皮肤病的可能原因。
Wnt signaling through the Frizzled (FZD) family of serpentine receptors is essential for embryogenesis and homeostasis, and stringent control of the FZD protein level is critical for stem cell regulation. Through CRISPR/Cas9 genome-wide screening in human cells, we identified TMEM79/MATTRIN, an orphan multi-span transmembrane protein, as a specific inhibitor of Wnt/FZD signaling. TMEM79 interacts with FZD during biogenesis and promotes FZD degradation independent of ZNRF3/RNF43 ubiquitin ligases (R-spondin receptors). TMEM79 interacts with ubiquitin-specific protease 8 (USP8), whose activating mutations underlie human tumorigenesis. TMEM79 specifically inhibits USP8 deubiquitination of FZD, thereby governing USP8 substrate specificity and promoting FZD degradation. Tmem79 and Usp8 genes have a pre-bilaterian origin, and Tmem79 inhibition of Usp8 and Wnt signaling is required for anterior neural development and gastrulation in Xenopus embryos. TMEM79 is a predisposition gene for Atopic dermatitis, suggesting deregulation of Wnt/FZD signaling a possible cause for this most common yet enigmatic inflammatory skin disease.