title: TOR-dependent post-transcriptional regulation of autophagy.
abstract: Regulation of autophagy is required to maintain cellular equilibrium and prevent disease. While extensive study of post-translational mechanisms has yielded important insights into autophagy induction, less is known about post-transcriptional mechanisms that could potentiate homeostatic control. In our study, we showed that the RNA-binding protein, Dhh1 in Saccharomyces cerevisiae and Vad1 in the pathogenic yeast Cryptococcus neoformans is involved in recruitment and degradation of key autophagy mRNAs. In addition, phosphorylation of the decapping protein Dcp2 by the target of rapamycin (TOR), facilitates decapping and degradation of autophagy-related mRNAs, resulting in repression of autophagy under nutrient-replete conditions. The post-transcriptional regulatory process is conserved in both mouse and human cells and plays a role in autophagy-related modulation of the inflammasome product IL1B. These results were then applied to provide mechanistic insight into autoimmunity of a patient with a PIK3CD/p110δ gain-of-function mutation. These results thus identify an important new post-transcriptional mechanism of autophagy regulation that is highly conserved between yeast and mammals.
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Guowu
authors.initials: G
authors.lastname: Hu
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Travis
authors.initials: T
authors.lastname: McQuiston
authors.affiliation: b Life Sciences Institute; University of Michigan ; Ann Arbor , MI USA.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bernard
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Yoon-Dong
authors.initials: YD
authors.lastname: Park
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: c Laboratory of Immunoregulation; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Vural
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Waterman
authors.affiliation: d Intramural Research Program in Genomics of Differentiation; National Institute of Child Health and Human Development; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Blewett
authors.affiliation: e Genomic Technologies Section; Research Technologies Branch; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.affiliation: d Intramural Research Program in Genomics of Differentiation; National Institute of Child Health and Human Development; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Maraia
authors.affiliation: c Laboratory of Immunoregulation; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: b Life Sciences Institute; University of Michigan ; Ann Arbor , MI USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: a Laboratory of Clinical Infectious Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health ; Bethesda , MD USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D006801:Humans; D020871:RNA Stability / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D053487:DEAD-box RNA Helicases
keywords: TOR; autoimmunity; autophagy; phosphorylation; translation