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: 10.43). 08/2009; 28(15):2244-58. DOI: 10.1038/emboj.2009.159
Source: PubMed


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.

Download full-text


Available from: Vojo Deretic
  • Source
    • "The first evidence of impaired autophagy in these models was provided by studies in mice and patients with mutations in collagen VI (Irwin et al., 2003). Mutations that inactivate Jumpy, a phosphatase that counteracts the activation of VPS34 for autophagosome formation and reduces autophagy, are associated with centronuclear myopathy (Vergne et al., 2009). De Palma et al. (2012) have described marked defect of autophagy in dystrophin-deficient mdx mice and DMD patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy.
    Full-text · Article · Aug 2014 · Frontiers in Aging Neuroscience
  • Source
    • "The molecular signaling pathway leading to autophagy is very complex and regulated by autophagy-related genes (Atgs), which are connected with the formation of autophagosomes (Hurley and Schulman, 2014). The protein products of Atgs are organized in five functional groups, namely: (i) the Unc-51-like kinase (Ulk):Atg13:FIP200 initiation complex (Ganley et al., 2009; Hosokawa et al., 2009); (ii) the beclin1:hVps34[phosphatidylinositol 3 (PI3) kinase]:Atg14L nucleation complex (Itakura et al., 2008); (iii) the PI3–phosphate- binding WIPI-1/2 complex (Proikas-Cezanne et al., 2004; Vergne et al., 2009); (iv) the Atg5–Atg12 conjugation complex activated by Atg7 (Mizushima et al., 1998); and (v) the Atg8 (LC3) conjugation system (Kabeya et al., 2000). These protein complexes participate at specific stages in the autophagic process: initiation, formation, elongation, and fusion (Mehrpour et al., 2010; Awan and Deng, 2014); they are also controlled by several other signaling pathways that fine tune autophagy to regulate the pace of autophagosome formation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. Autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates, and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels, it can be detrimental and contribute to muscle wasting; at low levels, it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular level, the Akt axis is one of the key dysregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signaling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.
    Full-text · Article · Jul 2014 · Frontiers in Aging Neuroscience
  • Source
    • "Atg9 also delivers membranes from trans-Golgi network/endosomes to the site of autophagosome biogenesis in an ULK1-and VPS34-dependent manner to promote the expansion of the autophagosome membrane [77]. The Atg12-Atg5-Atg16L complex only transiently attaches to the autophagosomal membranes and is later dissociated from the autophagosomal membranes [78], and PI3-P is also dephosphorylated locally by the phosphatases myotubularin-related protein 3 (MTMR3, also called Jumpy) upon closure of the autophagosomes [79] [80]; (4) finally, autophagosomes fuse with lysosomes/endosomes to form autolysosomes, which is mediated by Rab7, Lamp1/2, and the SNARE protein STX17 [81] [82] [83]. After fusion, the outer membrane of LC3-II is dissociated from the autolysosomal membrane through a deconjugation process mediated by Atg4B, and inner membrane LC3-II is degraded together with autophagosome cargos [84] [85]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.
    Full-text · Article · Jul 2014 · BioMed Research International
Show more