title: The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation.
abstract: The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1β production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1β resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ravindran
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Loebbermann
authors.affiliation: School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Helder I
authors.initials: HI
authors.lastname: Nakaya
authors.affiliation: Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: Nooruddin
authors.initials: N
authors.lastname: Khan
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Hualing
authors.initials: H
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Gama
authors.affiliation: Division of Pathology, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Deepa K
authors.initials: DK
authors.lastname: Machiah
authors.affiliation: Virology Core, Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Benton
authors.initials: B
authors.lastname: Lawson
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hakimpour
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Yi-Chong
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Shuzhao
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Pathology, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Degenerative Disease Research, Sanford |Burnham Medical Research Institute 10901 North Torrey Pines Road La Jolla, CA 92037 USA.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: National Institute of Environmental Health Sciences, Mail Drop D2-01 Research Triangle Park, NC 27709.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D003092:Colitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D053583:Interleukin-1beta / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D058504:Th17 Cells / Q000276:immunology; D044764:Ubiquitin-Activating Enzymes / Q000172:deficiency / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000596:Amino Acids; D000071187:Autophagy-Related Protein 5; D058847:Inflammasomes; D053583:Interleukin-1beta; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes