Gene deletion of Gabarap enhances Nlrp3 inflammasome-dependent inflammatory responses

J Immunol. 2013 Apr 1;190(7):3517-24. doi: 10.4049/jimmunol.1202628. Epub 2013 Feb 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Biological Transport
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cytoskeletal Proteins / genetics*
  • DNA, Mitochondrial / metabolism
  • Disease Models, Animal
  • Enzyme Activation
  • Gene Deletion*
  • Genes, Lethal
  • Genetic Predisposition to Disease
  • Inflammasomes*
  • Inflammation / genetics*
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / immunology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Mitophagy / genetics
  • Mitophagy / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species / metabolism
  • Sepsis / genetics
  • Sepsis / mortality


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA, Mitochondrial
  • GABARAP protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Caspase 1