Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy.

Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
The EMBO Journal (Impact Factor: 10.75). 08/2009; 28(15):2244-58. DOI: 10.1038/emboj.2009.159
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The myotubularins are a family of phosphoinositide 3-phosphatases preferentially hydrolyzing phosphatidylinositol 3-monophosphate and also phosphatidylinositol (3,5) bis-phosphate, thus generating phosphatidylinositol and phosphatidylinositol 5-monophosphate, respectively. These phosphoinositides are known regulators of vesicular trafficking and phosphatidylinositol 5-monophosphate was also implicated in signal transduction regulation. Based on their capacity to control the level of these phosphoinositides, myotubularins are involved in the regulation of vesicular trafficking, membrane homeostasis, cytoskeleton dynamics, proliferation and apoptosis. Myotubularin dysfunctions are linked to genetic diseases: MTMI is mutated in the X-linked congenital myotubular myopathy and MTMR2 and MTMR13 are mutated in autosomal recessive type 4B1 and 4B2 Charcot-Marie-Tooth neuropathies, respectively. This review presents the cellular functions of myotubularins and highlights their physiopathological roles in neuromuscular diseases.
    Clinical Lipidology 04/2012; 7(2):151-162. DOI:10.2217/clp.12.7 · 0.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phosphoinositides (PIs) are minor components of cellular membranes that play critical regulatory roles in several intracellular functions. This chapter describes the main enzymes regulating the turnover of each of the seven PIs in mammalian cells and introduces to some of their intracellular functions and to some evidences of their involvement in human diseases. Due to the complex interrelation between the distinct PIs and the plethora of functions that they can regulate inside a cell, this chapter is not meant to be a comprehensive coverage of all aspects of PI signalling but rather an introduction to this complex signalling field. For more details of their regulation/functions and extensive description of their intracellular roles, more detailed reviews are suggested on each single topic.
    Current topics in microbiology and immunology 01/2012; 362:1-42. DOI:10.1007/978-94-007-5025-8_1 · 3.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most of our knowledge on PTPs is derived from human pathologies and mouse knockout models. These models largely correlate well with human disease phenotypes, but can be ambiguous due to compensatory mechanisms introduced by paralogous genes. Here we present the analysis of the PTP complement of the fruit fly and the complementary view that PTP studies in Drosophila will accelerate our understanding of PTPs in physiological and pathological conditions. With only 44 PTP genes, Drosophila represents a streamlined version of the human complement. Our integrated analysis places the Drosophila PTPs into evolutionary and functional contexts, thereby providing a platform for the exploitation of the fly for PTP research and the transfer of knowledge onto other model systems. Copyright © 2015. Published by Elsevier B.V.
    FEBS Letters 03/2015; 589(9). DOI:10.1016/j.febslet.2015.03.005 · 3.34 Impact Factor