TORC1 Signaling Controls the Stability and Function of α-Arrestins Aly1 and Aly2.

Ray W Bowman, Eric M Jordahl, Sydnie Davis, Stefanie Hedayati, Hannah Barsouk, Nejla Ozbaki-Yagan, Annette Chiang, Yang Li, Allyson F O'Donnell

Biomolecules 2022 Mar 31

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Nutrient supply dictates cell signaling changes, which in turn regulate membrane protein trafficking. To better exploit nutrients, cells relocalize membrane transporters via selective protein trafficking. Key in this reshuffling are the α-arrestins, selective protein trafficking adaptors conserved from yeast to man. α-Arrestins bind membrane proteins, controlling the ubiquitination and endocytosis of many transporters. To prevent the spurious removal of membrane proteins, α-arrestin-mediated endocytosis is kept in check through phospho-inhibition. This phospho-regulation is complex, with up to 87 phospho-sites on a single α-arrestin and many kinases/phosphatases targeting α-arrestins. To better define the signaling pathways controlling paralogous α-arrestins, Aly1 and Aly2, we screened the kinase and phosphatase deletion (KinDel) library, which is an array of all non-essential kinase and phosphatase yeast deletion strains, for modifiers of Aly-mediated phenotypes. We identified many Aly regulators, but focused our studies on the TORC1 kinase, a master regulator of nutrient signaling across eukaryotes. We found that TORC1 and its signaling effectors, the Sit4 protein phosphatase and Npr1 kinase, regulate the phosphorylation and stability of Alys. When Sit4 is lost, Alys are hyperphosphorylated and destabilized in an Npr1-dependent manner. These findings add new dimensions to our understanding of TORC1 regulation of α-arrestins and have important ramifications for cellular metabolism.

Citation

Ray W Bowman, Eric M Jordahl, Sydnie Davis, Stefanie Hedayati, Hannah Barsouk, Nejla Ozbaki-Yagan, Annette Chiang, Yang Li, Allyson F O'Donnell. TORC1 Signaling Controls the Stability and Function of α-Arrestins Aly1 and Aly2. Biomolecules. 2022 Mar 31;12(4)