Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt.
Wingless (Wg)/Wnt has been proposed to exert various functions as a morphogen depending on the levels of its signalling. Therefore, not just the concentration of Wg/Wnt, but also the responsiveness of Wg/Wnt-target cells to the ligand, must have a crucial function in controlling cellular outputs. Here, we show that a balance of ubiquitylation and deubiquitylation of the Wg/Wnt receptor Frizzled determines the cellular responsiveness to Wg/Wnt both in mammalian cells and in Drosophila, and that the cell surface level of Frizzled is regulated by deubiquitylating enzyme UBPY/ubiquitin-specific protease 8 (USP8). Although ubiquitylated Frizzled underwent lysosomal trafficking and degradation, UBPY/USP8-dependent deubiquitylation led to recycling of Frizzled to the plasma membrane, thereby elevating its surface level. Importantly, a gain and loss of UBPY/USP8 function led to up- and down-regulation, respectively, of canonical Wg/Wnt signalling. These results unveil a novel mechanism that regulates the cellular responsiveness to Wg/Wnt by controlling the cell surface level of Frizzled.
Mukai
Akiko
A
Research Group of Glycobiology and Glycotechnology, Mitsubishi-Kagaku Institute of Life Sciences, Machida, Japan.
Yamamoto-Hino
Miki
M
Awano
Wakae
W
Watanabe
Wakako
W
Komada
Masayuki
M
Goto
Satoshi
S
D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000196:embryology* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004705:Endocytosis; D051157:Frizzled Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007814:Larva / Q000378:metabolism; D021381:Protein Transport; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination; D014921:Wings, Animal / Q000196:embryology / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051155:Wnt1 Protein / Q000378:metabolism*
D029721:Drosophila Proteins; D051157:Frizzled Receptors; D051153:Wnt Proteins; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; C000608556:USP8 protein, Drosophila; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases