title: Arf6 promotes autophagosome formation via effects on phosphatidylinositol 4,5-bisphosphate and phospholipase D.
abstract: Macroautophagy (in this paper referred to as autophagy) and the ubiquitin-proteasome system are the two major catabolic systems in cells. Autophagy involves sequestration of cytosolic contents in double membrane-bounded vesicles called autophagosomes. The membrane source for autophagosomes has received much attention, and diverse sources, such as the plasma membrane, Golgi, endoplasmic reticulum, and mitochondria, have been implicated. These may not be mutually exclusive, but the exact sources and mechanism involved in the formation of autophagosomes are still unclear. In this paper, we identify a positive role for the small G protein Arf6 in autophagosome formation. The effect of Arf6 on autophagy is mediated by its role in the generation of phosphatidylinositol 4,5-bisphosphate (PIP(2)) and in inducing phospholipase D (PLD) activity. PIP(2) and PLD may themselves promote autophagosome biogenesis by influencing endocytic uptake of plasma membrane into autophagosome precursors. However, Arf6 may also influence autophagy by indirect effects, such as either by regulating membrane flow from other compartments or by modulating PLD activity independently of the mammalian target of rapamycin.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 0XY, England, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Moreau
authors.forename: Brinda
authors.initials: B
authors.lastname: Ravikumar
authors.forename: Claudia
authors.initials: C
authors.lastname: Puri
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010588:Phagosomes / Q000187:drug effects / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; C115971:ARHGAP26 protein, human; C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D007166:Immunosuppressive Agents; D019269:Phosphatidylinositol 4,5-Diphosphate; D049452:Green Fluorescent Proteins; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020123:Sirolimus