title: Gene deletion of Gabarap enhances Nlrp3 inflammasome-dependent inflammatory responses.
abstract: The γ-aminobutyric acid A receptor-associated protein (Gabarap) functions in γ-aminobutyric acid A receptor trafficking and postsynaptic localization in neurons, but its physiological roles in other systems have not been studied. In this study, we report that Gabarap-deficient mice are more susceptible to mortality in two sepsis models. An underlying mechanism of this higher mortality rate in Gabarap(-/-) septic mice is the higher level of proinflammatory cytokine expression in Gabarap(-/-) mice versus wild-type mice. In vitro studies show that Nlrp3 inflammasome activation is enhanced by Gabarap deficiency, as evidenced by more casapse-1 activation, more IL-1β, and more IL-18 secretion in LPS- and ATP-treated Gabarap(-/-) macrophages. The Gabarap deficiency led to inefficient clearance of damaged mitochondria in LPS plus ATP-treated macrophages, resulting in more mitochondrial ROS and the release of mitochondrial DNA into cytosol. Both ROS and mitochondrial DNA are known to promote inflammasome activation. These results demonstrate that Gabarap functions in the immune system. It is involved in mitochondrial quality control in macrophages, and thus it influences Nlrp3 inflammasome-dependent inflammatory responses.
authors: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, 361005 Xiamen, Fujian, China.
authors: Zhirong
authors: Z
authors: Zhang
authors: Xiaozheng
authors: X
authors: Xu
authors: Jianhui
authors: J
authors: Ma
authors: Jianfeng
authors: J
authors: Wu
authors: Yanhai
authors: Y
authors: Wang
authors: Rongbin
authors: R
authors: Zhou
authors: Jiahuai
authors: J
authors: Han
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D017353:Gene Deletion; D005804:Genes, Lethal; D020022:Genetic Predisposition to Disease; D058847:Inflammasomes; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000401:mortality
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004272:DNA, Mitochondrial; C480861:GABARAP protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D020170:Caspase 1