title: A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy.
abstract: Autophagy is an essential eukaryotic pathway requiring tight regulation to maintain homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved mechanism of autophagy regulation by RNA helicase RCK family members in association with the decapping enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TOR-dependent phosphorylation and associates with RCK members to form a complex with autophagy-related (ATG) mRNA transcripts, leading to decapping, degradation and autophagy suppression. Simultaneous with the induction of ATG mRNA synthesis, starvation reverses the process, facilitating ATG mRNA accumulation and autophagy induction. This conserved post-transcriptional mechanism modulates fungal virulence and the mammalian inflammasome, the latter providing mechanistic insight into autoimmunity reported in a patient with a PIK3CD/p110δ gain-of-function mutation. We propose a dynamic model wherein RCK family members, in conjunction with Dcp2, function in controlling ATG mRNA stability to govern autophagy, which in turn modulates vital cellular processes affecting inflammation and microbial pathogenesis.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Guowu
authors.initials: G
authors.lastname: Hu
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Travis
authors.initials: T
authors.lastname: McQuiston
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bernard
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Yoon-Dong
authors.initials: YD
authors.lastname: Park
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Ali
authors.initials: A
authors.lastname: Vural
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Waterman
authors.affiliation: Intramural Research Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Blewett
authors.affiliation: Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA, 20892.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.affiliation: Intramural Research Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Maraia
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015966:Gene Expression Regulation, Fungal; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; C030052:mRNA decapping enzymes; D058543:Class Ia Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; C500749:target of rapamycin protein, S cerevisiae; C400572:DCP2 protein, S cerevisiae; D004722:Endoribonucleases; C445083:DHH1 protein, S cerevisiae; D053487:DEAD-box RNA Helicases