Roles for PI(3,5)P2 in nutrient sensing through TORC1

Article Article scientifique Article Roles for PI(3,5)P2 in nutrient sensing through TORC1 eng 2014 author Jin Natsuko author Mao Kai author Jin Yui author Tevzadze Gela Guram 668549 author Kauffman Emily J author Park Sujin author Bridges Dave author Loewith Robbie Joséph 630703 author Saltiel Alan R author Klionsky Daniel J author Weisman Lois S 1171-1185 10.1091/mbc.E14-01-0021 24478451 1059-1524 TORC1, a conserved protein kinase, regulates cell growth in response to nutrients. Localization of mammalian TORC1 to lysosomes is essential for TORC1 activation. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P(2)), an endosomal signaling lipid, is implicated in insulin-dependent stimulation of TORC1 activity in adipocytes. This raises the question of whether PI(3,5)P(2) is an essential general regulator of TORC1. Moreover, the subcellular location where PI(3,5)P(2) regulates TORC1 was not known. Here we report that PI(3,5)P(2) is required for TORC1 activity in yeast and regulates TORC1 on the vacuole (lysosome). Furthermore, we show that the TORC1 substrate, Sch9 (a homologue of mammalian S6K), is recruited to the vacuole by direct interaction with PI(3,5)P(2), where it is phosphorylated by TORC1. Of importance, we find that PI(3,5)P(2) is required for multiple downstream pathways via TORC1-dependent phosphorylation of additional targets, including Atg13, the modification of which inhibits autophagy, and phosphorylation of Npr1, which releases its inhibitory function and allows nutrient-dependent endocytosis. These findings reveal PI(3,5)P(2) as a general regulator of TORC1 and suggest that PI(3,5)P(2) provides a platform for TORC1 signaling from lysosomes. Autophagy Food Intracellular Membranes/metabolism Models Biological Phosphatidylinositol Phosphates/metabolism Phosphorylation Saccharomyces cerevisiae/cytology/metabolism Saccharomyces cerevisiae Proteins/metabolism Substrate Specificity Surface Plasmon Resonance Transcription Factors/metabolism Vacuoles/metabolism Dewey 570 Dewey 590 23 Institut de génétique et de génomique 0DH 43 Département de biologie moléculaire 161 false 814 Groupe Loewith Molecular Biology of the Cell 25 7 9ade0cb7-5a54-4187-a8db-899008acb6ab Article (Published version) Public MolBiolCell-2014-Jin-1171-85.pdf 4503427 application/pdf openAccess Centres et instituts / Institut de génétique et de génomique Faculté des sciences / Section de biologie / Département de biologie moléculaire

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Roles for PI(3,5)P2 in nutrient sensing through TORC1	Molecular Biology of the Cell			2014	512	193

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Tevzadze, Gela Guram