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The N‐end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin.
- Source :
- EMBO Journal; Jul2019, Vol. 38 Issue 13, pN.PAG-N.PAG, 1p, 4 Diagrams, 4 Graphs
- Publication Year :
- 2019
-
Abstract
- Anthrax lethal toxin (LT) is known to induce NLRP1B inflammasome activation and pyroptotic cell death in macrophages from certain mouse strains in its metalloprotease activity‐dependent manner, but the underlying mechanism is unknown. Here, we establish a simple but robust cell system bearing dual‐fluorescence reporters for LT‐induced ASC specks formation and pyroptotic lysis. A genome‐wide siRNA screen and a CRISPR‐Cas9 knockout screen were applied to this system for identifying genes involved in LT‐induced inflammasome activation. UBR2, an E3 ubiquitin ligase of the N‐end rule degradation pathway, was found to be required for LT‐induced NLRP1B inflammasome activation. LT is known to cleave NLRP1B after Lys44. The cleaved NLRP1B, bearing an N‐terminal leucine, was targeted by UBR2‐mediated ubiquitination and degradation. UBR2 partnered with an E2 ubiquitin‐conjugating enzyme UBE2O in this process. NLRP1B underwent constitutive autocleavage before the C‐terminal CARD domain. UBR2‐mediated degradation of LT‐cleaved NLRP1B thus triggered release of the noncovalent‐bound CARD domain for subsequent caspase‐1 activation. Our study illustrates a unique mode of inflammasome activation in cytosolic defense against bacterial insults. Synopsis: Anthrax lethal toxin cleaves its host sensor NLRP1B and causes inflammasome activation. Genetic screens identify the N‐end rule ubiquitin ligase UBR2 that mediates proteasomal degradation of the cleaved NLRP1B, causing the release of its CARD domain for caspase‐1 activation. siRNA and CRISPR‐Cas9 screens identify an N‐end rule ubiquitin ligase UBR2 that mediates anthrax lethal toxin‐induced NLRP1B inflammasome activation.UBR2 partners with UBE2O to induce proteasomal degradation of lethal toxin‐cleaved NLRP1B.UBR2‐mediated degradation releases NLRP1B CARD domain for caspase‐1 activation. [ABSTRACT FROM AUTHOR]
- Subjects :
- NLRP3 protein
ANTHRAX
UBIQUITIN-conjugating enzymes
TOXINS
GENETIC testing
CELL death
Subjects
Details
- Language :
- English
- ISSN :
- 02614189
- Volume :
- 38
- Issue :
- 13
- Database :
- Complementary Index
- Journal :
- EMBO Journal
- Publication Type :
- Academic Journal
- Accession number :
- 137267014
- Full Text :
- https://doi.org/10.15252/embj.2019101996