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

Andrew Sandstrom, Patrick S. Mitchell, Lisa Goers, Edward W. Mu, Cammie F. Lesser, Russell E. Vance
doi: https://doi.org/10.1101/317834
Andrew Sandstrom
Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, California, USAHoward Hughes Medical Institute, University of California, Berkeley, California, USA
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Patrick S. Mitchell
Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, California, USA
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Lisa Goers
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
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Edward W. Mu
Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, California, USA
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Cammie F. Lesser
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USADepartment of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, Massachusetts, USA
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Russell E. Vance
Division of Immunology & Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, California, USAHoward Hughes Medical Institute, University of California, Berkeley, California, USA
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  • For correspondence: rvance@berkeley.edu
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Abstract

Inflammasomes are multi-protein 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. Here we find that cleavage results in proteasome-mediated degradation of the N-terminal domains of NLRP1B, liberating a C-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 new ‘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.

One Sentence Summary Two distinct pathogen enzymes activate an innate immune sensor called NLRP1B by a mechanism that requires proteasome-mediated degradation of NLRP1B.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 09, 2018.
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Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes
Andrew Sandstrom, Patrick S. Mitchell, Lisa Goers, Edward W. Mu, Cammie F. Lesser, Russell E. Vance
bioRxiv 317834; doi: https://doi.org/10.1101/317834
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Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes
Andrew Sandstrom, Patrick S. Mitchell, Lisa Goers, Edward W. Mu, Cammie F. Lesser, Russell E. Vance
bioRxiv 317834; doi: https://doi.org/10.1101/317834

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