Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

Science. 2019 Apr 5;364(6435):eaau1330. doi: 10.1126/science.aau1330. Epub 2019 Mar 14.

Abstract

Inflammasomes are multiprotein platforms that initiate innate immunity by recruitment and activation of caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our functional degradation model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, Bacterial / metabolism*
  • Apoptosis Regulatory Proteins / metabolism*
  • Bacillus anthracis / enzymology
  • Bacterial Proteins / metabolism*
  • Bacterial Toxins / metabolism
  • CARD Signaling Adaptor Proteins / chemistry
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspase 1 / metabolism
  • Death Domain Receptor Signaling Adaptor Proteins / chemistry
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Enzyme Activation
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate*
  • Inflammasomes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Peptide Hydrolases / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Domains
  • Protein Subunits
  • Proteolysis*
  • RAW 264.7 Cells
  • Shigella flexneri / enzymology
  • Shigella flexneri / pathogenicity*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Bacterial
  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • Bacterial Toxins
  • CARD Signaling Adaptor Proteins
  • CARD8 protein, human
  • Death Domain Receptor Signaling Adaptor Proteins
  • Inflammasomes
  • NLRP1 protein, human
  • Neoplasm Proteins
  • PIDD1 protein, human
  • Protein Subunits
  • anthrax toxin
  • ipaH protein, Shigella flexneri
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Caspase 1
  • Proteasome Endopeptidase Complex