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Elife January 1, 2020; 9

TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis.

Chen M , Amado N , Tan J , Reis A , Ge M , Abreu JG , He X .

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.

PubMed ID: 32924931
PMC ID: PMC7521923
Article link: Elife
Grant support: [+]
Genes referenced: ag1 apc banf1 bmp4 calr chrd.1 chsy1 csnk1a1 ctnnb1 ddx17 dkk1 dvl2 eea1 egr2 en2 fgf2 foxa2 foxd3 foxg1 fzd1 fzd10 fzd5 fzd9 gli1 golph3 gsc gsk3b isyna1 krt12.4 lamp1 lhx1 lrp6 lrp8 map6 myc nodal1 nodal3.1 nog nol8 not nwd1 otx2 ptch1 rnf43 sdad1 shh six3 smo snai1 sox2 sytl4 tbxt tmem79 top3a tubb2b ubr5 usp8 ventx2.2 wnt3a znrf3
Morpholinos: tmem79 MO1 tmem79 MO2 usp8 MO1

Disease Ontology terms: spina bifida

Article Images: [+] show captions

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