title: Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy.
abstract: The majority of studies on autophagy, a cytoplasmic homeostasis 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.
authors: Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. ivergne@salud.unm.edu
authors: Isabelle
authors: I
authors: Vergne
authors: Esteban
authors: E
authors: Roberts
authors: Rasha A
authors: RA
authors: Elmaoued
authors: Valérie
authors: V
authors: Tosch
authors: Mónica A
authors: MA
authors: Delgado
authors: Tassula
authors: T
authors: Proikas-Cezanne
authors: Jocelyn
authors: J
authors: Laporte
authors: Vojo
authors: V
authors: Deretic
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA
chemical_list: C515634:MTMR14 protein, human; D010744:Phosphoric Monoester Hydrolases