title: WIPI1 coordinates melanogenic gene transcription and melanosome formation via TORC1 inhibition.
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.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697-2400, USA.
authors.forename: Hsiang
authors.initials: H
authors.lastname: Ho
authors.forename: Rubina
authors.initials: R
authors.lastname: Kapadia
authors.forename: Sejad
authors.initials: S
authors.lastname: Al-Tahan
authors.forename: Safoora
authors.initials: S
authors.lastname: Ahmad
authors.forename: Anand K
authors.initials: AK
authors.lastname: Ganesan
mesh_terms: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020460:Melanosomes / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; C500984:CRTC1 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors; C522812:WIPI1 protein, human; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus