title: A diacylglycerol-dependent signaling pathway contributes to regulation of antibacterial autophagy.
abstract: Autophagy mediates the degradation of cytoplasmic contents in the lysosome and plays a significant role in immunity. Lipid second messengers have previously been implicated in the regulation of autophagy. Here, we demonstrate a signaling role for diacylglycerol (DAG) in antibacterial autophagy. DAG production was necessary for efficient autophagy of Salmonella, and its localization to bacteria-containing phagosomes preceded autophagy. The actions of phospholipase D and phosphatidic acid phosphatase were required for DAG generation and autophagy. Furthermore, the DAG-responsive delta isoform of protein kinase C was required, as were its downstream targets JNK and NADPH oxidase. Previous studies have revealed a role for the ubiquitin-binding adaptor molecules p62 and NDP52 in autophagy of S. Typhimurium. We observed bacteria-containing autophagosomes colocalizing individually with either DAG or ubiquitinated proteins, indicating that both signals can act independently to promote antibacterial autophagy. These findings reveal an important role for DAG-mediated PKC function in mammalian antibacterial autophagy.
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Shahab
authors.initials: S
authors.lastname: Shahnazari
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Yen
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Birmingham
authors.forename: Jessica
authors.initials: J
authors.lastname: Shiu
authors.forename: Anton
authors.initials: A
authors.lastname: Namolovan
authors.forename: Yiyu T
authors.initials: YT
authors.lastname: Zheng
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D004075:Diglycerides / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D010711:Phosphatidate Phosphatase / Q000502:physiology; D010739:Phospholipase D / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D004075:Diglycerides; D011493:Protein Kinase C; D010711:Phosphatidate Phosphatase; D010739:Phospholipase D