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New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation

Jeannette L. Tenthorey, Roberto A. Chavez, Thornton W. Thompson, Katherine A. Deets, Russell E. Vance, View ORCID ProfileIsabella Rauch
doi: https://doi.org/10.1101/765313
Jeannette L. Tenthorey
1Molecular and Cell Biology Department, Immunology and Pathogenesis Division, and Cancer Research Laboratory, University of California, Berkeley, USA
2Current address: Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Roberto A. Chavez
1Molecular and Cell Biology Department, Immunology and Pathogenesis Division, and Cancer Research Laboratory, University of California, Berkeley, USA
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Thornton W. Thompson
1Molecular and Cell Biology Department, Immunology and Pathogenesis Division, and Cancer Research Laboratory, University of California, Berkeley, USA
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Katherine A. Deets
1Molecular and Cell Biology Department, Immunology and Pathogenesis Division, and Cancer Research Laboratory, University of California, Berkeley, USA
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Russell E. Vance
1Molecular and Cell Biology Department, Immunology and Pathogenesis Division, and Cancer Research Laboratory, University of California, Berkeley, USA
3Howard Hughes Medical Institute, University of California, Berkeley, USA
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Isabella Rauch
4Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR, USA
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  • ORCID record for Isabella Rauch
  • For correspondence: rauchi@ohsu.edu
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ABSTRACT

The NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new Nlrc4-deficient mouse line as well as mice encoding phosphomimetic S533D and non-phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.

Copyright 
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 September 18, 2019.
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New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation
Jeannette L. Tenthorey, Roberto A. Chavez, Thornton W. Thompson, Katherine A. Deets, Russell E. Vance, Isabella Rauch
bioRxiv 765313; doi: https://doi.org/10.1101/765313
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New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation
Jeannette L. Tenthorey, Roberto A. Chavez, Thornton W. Thompson, Katherine A. Deets, Russell E. Vance, Isabella Rauch
bioRxiv 765313; doi: https://doi.org/10.1101/765313

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