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PMID: 24478451 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Molecular biology of the cell ·Vol. 25 ·No. 7 ·2014-04-00 ·Pages 1171-85

Jin N, Mao K, Jin Y, Tevzadze G, Kauffman EJ, Park S, Bridges D, Loewith R, Saltiel AR, Klionsky DJ, Weisman LS

Abstract

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.

MeSH Terms
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
Chemicals
Phosphatidylinositol Phosphates Saccharomyces cerevisiae Proteins TORC1 protein complex, S cerevisiae Transcription Factors phosphatidylinositol 3,5-diphosphate
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Jin Natsuko
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109 Department of Molecular, Cellular, and Developmental Biology and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 Department of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 Department of Molecular Biology, University of Geneva, Geneva 1211, Switzerland Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109.
Mao Kai
Jin Yui
Tevzadze Gela
Kauffman Emily J
Park Sujin
Bridges Dave
Loewith Robbie
Saltiel Alan R
Klionsky Daniel J
Weisman Lois S
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.E14-01-0021
Published
2014-04-00
Epub
2014-00-29
Pages
1171-85
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC3967979
Subset
IM
Grants
NIGMS NIH HHS · GM053396 · United States
NIDDK NIH HHS · R01 DK061618 · United States
NIGMS NIH HHS · R01 GM053396 · United States
NIDDK NIH HHS · 5R01DK061618 · United States
NIGMS NIH HHS · R01 GM050403 · United States
NIGMS NIH HHS · R01-GM50403 · United States
External Links
PubMed source DOI: 10.1091/mbc.E14-01-0021 PMC Full Text View journal details
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