STRUCTURAL AND FUNCTIONAL DETERMINANTS OF CASPASE-11 INFLAMMASOME ASSEMBLY DURING INNATE IMMUNE DEFENSE

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Degree type
PhD
Graduate group
Cell and Molecular Biology
Discipline
Microbiology
Immunology and Infectious Disease
Biochemistry, Biophysics, and Structural Biology
Subject
autoprocessing
Caspase-11
inflammasome
lipopolysaccharide
non canonical
pyroptosis
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Copyright date
01/01/2022
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Author
Akuma, Daniel, C
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Abstract

Caspase-11 (Casp11) is a pattern-recognition receptor that senses cytosolic LPS. In response to binding cytosolic LPS, Casp11 assembles into a supramolecular organizing center (SMOC) designated the noncanonical inflammasome, where it is thought to undergo proximity-induced autoprocessing and become activated to mediate pyroptosis. Casp11 inflammasome assembly contributes to anti-microbial host defense but causes sepsis in murine models when dysregulated. To better understand noncanonical inflammasome dynamics within cells, we tracked LPS-inducible assembly of fluorescent-tagged Casp11 in primary macrophages. Unexpectedly, catalytic activity was required for LPS-induced Casp11 assembly in macrophages. Moreover, both catalytic activity and autoprocessing were required for Casp11 oligomerization in an ectopic expression system, suggesting that catalytic activity and autoprocessing occur upstream of, and mediate, Casp11 oligomerization. Critically, TEV-cleavable Casp11 could undergo TEV-induced oligomerization only in the presence of the catalytic cysteine. Further, wild-type Casp11 rescued speck formation of catalytically inactive Casp11 in a manner that required autoprocessing of the wild-type partner, but not of the catalytically inactive Casp11. Our data reveal a previously undescribed role for Casp11 catalytic activity and intra-molecular self-cleavage in noncanonical inflammasome assembly.

Advisor
Brodsky, Igor, E
Date of degree
2022
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