The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes

Sci Rep. 2018 May 31;8(1):8446. doi: 10.1038/s41598-018-26603-1.

Abstract

Activation of the inflammasome pathway is crucial for effective intracellular host defense. The mitochondrial network plays an important role in inflammasome regulation but the mechanisms linking mitochondrial homeostasis to attenuation of inflammasome activation are not fully understood. Here, we report that the Parkinson's disease-associated mitochondrial serine protease HtrA2 restricts the activation of ASC-dependent NLRP3 and AIM2 inflammasomes, in a protease activity-dependent manner. Consistently, disruption of the protease activity of HtrA2 results in exacerbated NLRP3 and AIM2 inflammasome responses in macrophages ex vivo and systemically in vivo. Mechanistically, we show that the HtrA2 protease activity regulates autophagy and controls the magnitude and duration of inflammasome signaling by preventing prolonged accumulation of the inflammasome adaptor ASC. Our findings identify HtrA2 as a non-redundant mitochondrial quality control effector that keeps NLRP3 and AIM2 inflammasomes in check.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Bone Marrow Cells / cytology
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • High-Temperature Requirement A Serine Peptidase 2 / deficiency
  • High-Temperature Requirement A Serine Peptidase 2 / genetics
  • High-Temperature Requirement A Serine Peptidase 2 / metabolism*
  • Inflammasomes / metabolism*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*

Substances

  • Aim2 protein, mouse
  • CARD Signaling Adaptor Proteins
  • DNA-Binding Proteins
  • Inflammasomes
  • Inhibitor of Apoptosis Proteins
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pycard protein, mouse
  • High-Temperature Requirement A Serine Peptidase 2
  • Htra2 protein, mouse
  • Caspase 1