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PMID: 21317285 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

WIPI1 coordinates melanogenic gene transcription and melanosome formation via TORC1 inhibition.

The Journal of biological chemistry ·Vol. 286 ·No. 14 ·2011-04-08 ·Pages 12509-23

Ho H, Kapadia R, Al-Tahan S, Ahmad S, Ganesan AK

Abstract

Recent studies implicate a role for WD repeat domain, phosphoinositide-interacting 1 (WIPI1) in the biogenesis of melanosomes, cell type-specific lysosome-related organelles. In this study, we determined that WIPI1, an ATG18 homologue that is shown to localize to both autophagosomes and early endosomes, inhibited mammalian target of rapamycin (MTOR) signaling, leading to increased transcription of melanogenic enzymes and the formation of mature melanosomes. WIPI1 suppressed the target of rapamycin complex 1 (TORC1) activity, resulting in glycogen synthase kinase 3β inhibition, β-Catenin stabilization, and increased transcription of microphthalmia transcription factor and its target genes. WIPI1-depleted cells accumulated stage I melanosomes but lacked stage III-IV melanosomes. Inhibition of TORC1 by rapamycin treatment resulted in the accumulation of stage IV melanosomes but not autophagosomes, whereas starvation resulted in the formation of autophagosomes but not melanin accumulation. Taken together, our studies define a distinct role for WIPI1 and TORC1 signaling in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy.

MeSH Terms
Autophagy-Related Proteins Carrier Proteins/genetics,metabolism Cell Line, Tumor Chromatin Immunoprecipitation Glycogen Synthase Kinase 3/genetics,metabolism Glycogen Synthase Kinase 3 beta Humans Melanosomes/metabolism,ultrastructure Membrane Proteins Microphthalmia-Associated Transcription Factor/genetics,metabolism Microscopy, Electron, Transmission Microscopy, Fluorescence Polymerase Chain Reaction Protein Binding RNA Interference Signal Transduction/drug effects Sirolimus/pharmacology Transcription Factors/antagonists & inhibitors,genetics,metabolism beta Catenin/genetics,metabolism
Chemicals
Autophagy-Related Proteins CRTC1 protein, human Carrier Proteins Membrane Proteins Microphthalmia-Associated Transcription Factor Transcription Factors WIPI1 protein, human beta Catenin GSK3B protein, human Glycogen Synthase Kinase 3 beta Glycogen Synthase Kinase 3 Sirolimus
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ho Hsiang
Department of Biological Chemistry, University of California, Irvine, CA 92697-2400, USA.
Kapadia Rubina
Al-Tahan Sejad
Ahmad Safoora
Ganesan Anand K
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M110.200543
Published
2011-04-08
Epub
2011-00-11
Pages
12509-23
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3069453
Subset
IM
Grants
NIAMS NIH HHS · R03 AR057150 · United States
NIAMS NIH HHS · K08 AR056001 · United States
NIAMS NIH HHS · 1K08AR056001 · United States
NIAMS NIH HHS · 1R03AR057150 · United States
NCRR NIH HHS · P41-RR01192 · United States
NCRR NIH HHS · P41 RR001192 · United States
NCI NIH HHS · P30 CA062203 · United States
External Links
PubMed source DOI: 10.1074/jbc.M110.200543 PMC Full Text View journal details
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