The N‐end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin
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‐f...
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Published in | The EMBO journal Vol. 38; no. 13 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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Blackwell Publishing Ltd
01.07.2019
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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.
Loss‐of‐function screens in combination with new pyroptosis reporter systems reveal that the anthrax lethal toxin metalloprotease collaborates with a cellular E3 ligase for proteolytic release of an inflammasomal CARD domain inducing downstream caspase‐1 activation. |
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AbstractList | 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. 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. Loss‐of‐function screens in combination with new pyroptosis reporter systems reveal that the anthrax lethal toxin metalloprotease collaborates with a cellular E3 ligase for proteolytic release of an inflammasomal CARD domain inducing downstream caspase‐1 activation. |
Author | Gao, Hang Xu, Hao Liu, Ying Yang, Zhenxiao Dong, Na Shao, Feng Shi, Jianjin |
Author_xml | – sequence: 1 givenname: Hao surname: Xu fullname: Xu, Hao organization: National Institute of Biological Sciences – sequence: 2 givenname: Jianjin surname: Shi fullname: Shi, Jianjin organization: National Institute of Biological Sciences – sequence: 3 givenname: Hang surname: Gao fullname: Gao, Hang organization: China Agricultural University – sequence: 4 givenname: Ying surname: Liu fullname: Liu, Ying organization: China Agricultural University – sequence: 5 givenname: Zhenxiao surname: Yang fullname: Yang, Zhenxiao organization: National Institute of Biological Sciences – sequence: 6 givenname: Feng orcidid: 0000-0002-9562-7791 surname: Shao fullname: Shao, Feng email: shaofeng@nibs.ac.cn organization: Tsinghua University – sequence: 7 givenname: Na orcidid: 0000-0003-2093-4719 surname: Dong fullname: Dong, Na email: dongna@cau.edu.cn organization: China Agricultural University |
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SubjectTerms | Anthrax Anthrax lethal toxin Bearing Biodegradation Caspase Cell activation Cell death CRISPR Degradation Fluorescence Genetic screening Genomes Inflammasomes Leucine Lysis Macrophages Metalloproteinase NLRP1B inflammasome N‐end rule pathway Proteasomes siRNA Toxins Ubiquitin Ubiquitin-protein ligase Ubiquitination UBR2 |
Title | The N‐end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin |
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