title: Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis.
abstract: BACKGROUND
  Autophagy is a fundamental cell biological process whereby eukaryotic cells form membranes in the cytoplasm to sequester diverse intracellular targets. Although significant progress has been made in understanding the origins of autophagosomal organelles, the source of lipids that support autophagic membrane formation remain an important open question.
  
  
  RESULTS
  Here we show that lipid droplets as cellular stores of neutral lipids including triglycerides contribute to autophagic initiation. Lipid droplets, as previously shown, were consumed upon induction of autophagy by starvation. However, inhibition of autophagic maturation by blocking acidification or using dominant negative Atg4(C74A) that prohibits autophagosomal closure did not prevent disappearance of lipid droplets. Thus, lipid droplets continued to be utilized upon induction of autophagy, but not as autophagic substrates in a process referred to as lipophagy. We considered an alternative model whereby lipid droplets were consumed not as a part of lipophagy, but as a potential contributing source to the biogenesis of lipid precursors for nascent autophagosomes. We carried out a screen for a potential link between triglyceride mobilization and autophagy and identified a neutral lipase, PNPLA5, as being required for efficient autophagy. PNPLA5, which localized to lipid droplets, was needed for optimal initiation of autophagy. PNPLA5 was required for autophagy of diverse substrates, including degradation of autophagic adaptors, bulk proteolysis, mitochondrial quantity control, and microbial clearance.
  
  
  CONCLUSIONS
  Lipid droplets contribute to autophagic capacity by enhancing it in a process dependent on PNPLA5. Thus, neutral lipid stores are mobilized during autophagy to support autophagic membrane formation.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA; INEM, INSERM U1151, CNRS UMR8253, Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75014 Paris France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupont
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Chauhan
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA.
authors.forename: John
authors.initials: J
authors.lastname: Arko-Mensah
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA.
authors.forename: Eliseo F
authors.initials: EF
authors.lastname: Castillo
authors.affiliation: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Andrius
authors.initials: A
authors.lastname: Masedunskas
authors.affiliation: Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.affiliation: Leibniz-Institute for Arteriosclerosis Research, University of Muenster, 48149 Münster, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Robenek
authors.affiliation: Autophagy Laboratory, Department of Molecular Biology, University of Tuebingen, Auf der Morgenstelle 15, 72076 Tuebingen, Germany.
authors.forename: Tassula
authors.initials: T
authors.lastname: Proikas-Cezanne
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA. Electronic address: vderetic@salud.unm.edu.
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008049:Lipase / Q000502:physiology*; D008055:Lipids / Q000502:physiology*; D019301:Oleic Acid / Q000378:metabolism; D010588:Phagosomes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism / Q000502:physiology; D000217:Acyltransferases
chemical_list: D008243:1-Acylglycerophosphocholine O-Acyltransferase; D008049:Lipase; D008055:Lipids; D019301:Oleic Acid; D014280:Triglycerides; C586147:LPCAT2 protein, human; C549685:PNPLA5 protein, human; D000217:Acyltransferases