The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation

J Biol Chem. 2014 Nov 21;289(47):32926-36. doi: 10.1074/jbc.M114.579961. Epub 2014 Oct 6.

Abstract

Lysosome rupture triggers NLRP3 inflammasome activation in macrophages. However, the underlying mechanism is not fully understood. Here we showed that the TAK1-JNK pathway, a MAPK signaling pathway, is activated through lysosome rupture and that this activation is necessary for the complete activation of the NLRP3 inflammasome through the oligomerization of an adapter protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). We also revealed that the activation of the TAK1-JNK pathway is sustained through Ca(2+) ions and that calcium/calmodulin-dependent protein kinase type II functions upstream of the TAK1-JNK pathway and specifically regulates lysosome rupture-induced NLRP3 inflammasome activation. These data suggest a novel role for the TAK1-JNK pathway as a critical regulator of NLRP3 inflammasome activation.

Keywords: Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII); Inflammasome; Innate Immunity; Lysosome Rupture; Mitogen-activated Protein Kinase (MAPK); NLRP3; Signal Transduction; TAK1; c-Jun N-terminal Kinase (JNK); siRNA Screen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CARD Signaling Adaptor Proteins
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Inflammasomes / metabolism*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Lysosomes / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System*
  • Microscopy, Fluorescence
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Multimerization
  • RNA Interference

Substances

  • AIM2 protein, human
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Calcium