Article
- The EMBO Journal (2009) 28, 2244 - 2258
- doi:10.1038/emboj.2009.159
Published online: 9 July 2009
Subject Categories:
Control of autophagy initiation by phosphoinositide 3-phosphatase jumpy
Isabelle Vergne1, Esteban Roberts1, Rasha A Elmaoued1, Valérie Tosch2, Mónica A Delgado1, Tassula Proikas-Cezanne3, Jocelyn Laporte2 and Vojo Deretic1,4
- Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA
- Departments of Neurobiology and Genetics, IGBMC, INSERM U596, CNRS UMR, Université Louis Pasteur de Strasbourg, Collège de France, Illkirch, France
- Department of Molecular Biology, University of Tuebingen, Tuebingen, Germany
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM, USA
Correspondence to:
Isabelle Vergne, Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Health Sciences Center, 915 Camino de Salud, Albuquerque, NM 87131-001, USA. Tel.: +1 505 272 9579; Fax: +1 505 272 6029; E-mail: ivergne@salud.unm.edu
Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Health Sciences Center, 915 Camino de Salud, Albuquerque, NM 87131-001, USA. Tel.: +1 505 272 0291; Fax: +1 505 272 5309; E-mail: vderetic@salud.unm.edu
Received 11 January 2009; Accepted 18 May 2009
Abstract
The majority of studies on autophagy, a cytoplasmic homeostatis pathway of broad biological and medical significance, have been hitherto focused on the phosphatidylinositol 3-kinases as the regulators of autophagy. Here, we addressed the reverse process driven by phosphoinositide phosphatases and uncovered a key negative regulatory role in autophagy of a phosphatidylinositol 3-phosphate (PI3P) phosphatase Jumpy (MTMR14). Jumpy associated with autophagic isolation membranes and early autophagosomes, defined by the key factor Atg16 necessary for proper localization and development of autophagic organelles. Jumpy orchestrated orderly succession of Atg factors by controlling recruitment to autophagic membranes of the sole mammalian Atg factor that interacts with PI3P, WIPI-1 (Atg18), and by affecting the distribution of Atg9 and LC3, the two Atg factors controlling organization and growth of autophagic membranes. A catalytically inactive Jumpy mutant, R336Q, found in congenital disease centronuclear myopathy, lost the ability to negatively regulate autophagy. This work reports for the first time that initiation of autophagy is controlled not only by the forward reaction of generating PI3P through a lipid kinase but that its levels are controlled by a specific PI3P phosphatase, which when defective can lead to human disease.
Keywords:
- Atg18,
- autophagy,
- LC3,
- myopathy,
- PI3P phosphatase
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