F. M. Kirby Neurobiology Center, Boston Children's Hospital, Department of Neurology, Harvard Medical School, Boston, United States.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Elife. 2020 Sep 14;9:e56793. doi: 10.7554/eLife.56793.
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 biquitin-pecific rotease 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 embryos. 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.
卷曲受体家族（FZD）通过 Wnt 信号通路对胚胎发生和体内平衡至关重要，严格控制 FZD 蛋白水平对于干细胞调节至关重要。通过人类细胞的 CRISPR/Cas9 全基因组筛选，我们鉴定出孤儿多跨膜蛋白 TMEM79/MATTRIN 是 Wnt/FZD 信号的特异性抑制剂。TMEM79 在生物发生过程中与 FZD 相互作用，并促进 FZD 降解，而不依赖于 ZNRF3/RNF43 泛素连接酶（R- 分泌蛋白受体）。TMEM79 与泛素特异性蛋白酶 8（USP8）相互作用，人类肿瘤发生的基础是其激活突变。TMEM79 特异性抑制 USP8 对 FZD 的去泛素化，从而控制 USP8 底物特异性并促进 FZD 降解。Tmem79 和 Usp8 基因具有原双侧起源，并且 Tmem79 抑制 Usp8 和 Wnt 信号通路对于 胚胎的前神经发育和原肠胚形成是必需的。 是特应性皮炎的易感性基因，这表明 Wnt/FZD 信号的失调可能是这种最常见但神秘的炎症性皮肤病的原因。
