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Regulation of the NLRP1 and CARD8 In...

Hsiao, Chieh,

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Regulation of the NLRP1 and CARD8 Inflammasomes /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation of the NLRP1 and CARD8 Inflammasomes // Chieh Hsiao.
作者:	Hsiao, Chieh,
面頁冊數:	1 electronic resource (124 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
Contained By:	Dissertations Abstracts International86-02B.
標題:	Immunology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31489591
ISBN:	9798384015000

Regulation of the NLRP1 and CARD8 Inflammasomes /
Hsiao, Chieh,

Regulation of the NLRP1 and CARD8 Inflammasomes /Chieh Hsiao. - 1 electronic resource (124 pages)

Source: Dissertations Abstracts International, Volume: 86-02, Section: B.

Several intracellular danger-associated signals induce the assembly of multiprotein complexes called inflammasomes. The typical process of inflammasome formation involves a pattern recognition receptor protein detecting a specific danger signal, self-oligomerizing, and recruiting the cysteine protease caspase-1 (CASP1). CASP1 then undergoes proximity-induced autoproteolysis, generating an active enzyme that cleaves and activates gasdermin D (GSDMD) and cytokines. The N-terminal fragment of cleaved GSDMD then forms pores in the cell membrane, releasing the activated cytokines and triggering pyroptotic cell death. This cascade is tightly regulated to prevent aberrant activation and associated autoinflammatory diseases.While the primordial functions of the NLRP1 and CARD8 inflammasomes have not been definitively established, we have hypothesized that they have evolved to sense a pathogen-induced "damage state" related to peptides cleaved by dipeptidyl peptidases 8/9 (DPP8/9). Whether additional stresses to DPP8/9 inhibition contribute to this damage state has not been identified.Here, we first characterize the molecular basis behind the DPP8/9 inhibitor-induced proteasome degradation pathway. We found that the core 20S proteasome, which degrades misfolded proteins independent of the 19S regulatory complex and ubiquitination, regulates CARD8 activation. Under DPP8/9-inhibition-induced stress, the 20S degrades CARD8's entire NT fragment, releasing the inflammatory CT fragment from autoinhibition. These results underscore the importance of CARD8's NT as a sensor of proteotoxicity.We have previously shown that thioredoxin (TRX1) restrains the activation of the NLRP1 inflammasome by their physical interactions. Here, we identify a key regulatory mechanism that governs the interaction between TRX1 and NLRP1. We show that a disulfide bond forms between cysteine residue 427 of NLRP1 and cysteine residue 32 of TRX1. These results highlight the NLRP1's NT as a sensor of redox stress.Lastly, we demonstrate that DPP9 itself binds to KEAP1, a cysteine-rich protein that controls NRF2, the regulator of the cellular antioxidant defense system. We characterize a mutually inhibitory relationship between the two proteins: KEAP1 binding inhibits DPP9's catalytic activity, while DPP9 binding prevents KEAP1 from degrading NRF2. Importantly, we reveal that KEAP1- bound DPP9 is incapable of restraining the inflammasome. Collectively, these three findings reveal unique sensory inputs that govern the activations of the CARD8 and NLRP1 inflammasomes.

English

ISBN: 9798384015000Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Inflammasomes

Regulation of the NLRP1 and CARD8 Inflammasomes /
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500 $a Advisors: Bachovchin, Daniel A. Committee members: Jiang, Xuejun; An, Heeseon; Zhou, Pengbo; Dar, Arvin C.
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520 $a Several intracellular danger-associated signals induce the assembly of multiprotein complexes called inflammasomes. The typical process of inflammasome formation involves a pattern recognition receptor protein detecting a specific danger signal, self-oligomerizing, and recruiting the cysteine protease caspase-1 (CASP1). CASP1 then undergoes proximity-induced autoproteolysis, generating an active enzyme that cleaves and activates gasdermin D (GSDMD) and cytokines. The N-terminal fragment of cleaved GSDMD then forms pores in the cell membrane, releasing the activated cytokines and triggering pyroptotic cell death. This cascade is tightly regulated to prevent aberrant activation and associated autoinflammatory diseases.While the primordial functions of the NLRP1 and CARD8 inflammasomes have not been definitively established, we have hypothesized that they have evolved to sense a pathogen-induced "damage state" related to peptides cleaved by dipeptidyl peptidases 8/9 (DPP8/9). Whether additional stresses to DPP8/9 inhibition contribute to this damage state has not been identified.Here, we first characterize the molecular basis behind the DPP8/9 inhibitor-induced proteasome degradation pathway. We found that the core 20S proteasome, which degrades misfolded proteins independent of the 19S regulatory complex and ubiquitination, regulates CARD8 activation. Under DPP8/9-inhibition-induced stress, the 20S degrades CARD8's entire NT fragment, releasing the inflammatory CT fragment from autoinhibition. These results underscore the importance of CARD8's NT as a sensor of proteotoxicity.We have previously shown that thioredoxin (TRX1) restrains the activation of the NLRP1 inflammasome by their physical interactions. Here, we identify a key regulatory mechanism that governs the interaction between TRX1 and NLRP1. We show that a disulfide bond forms between cysteine residue 427 of NLRP1 and cysteine residue 32 of TRX1. These results highlight the NLRP1's NT as a sensor of redox stress.Lastly, we demonstrate that DPP9 itself binds to KEAP1, a cysteine-rich protein that controls NRF2, the regulator of the cellular antioxidant defense system. We characterize a mutually inhibitory relationship between the two proteins: KEAP1 binding inhibits DPP9's catalytic activity, while DPP9 binding prevents KEAP1 from degrading NRF2. Importantly, we reveal that KEAP1- bound DPP9 is incapable of restraining the inflammasome. Collectively, these three findings reveal unique sensory inputs that govern the activations of the CARD8 and NLRP1 inflammasomes.
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650 4 $a Immunology. $3 611031
650 4 $a Biochemistry. $3 518028
650 4 $a Pharmacology. $3 634543
653 $a Inflammasomes
653 $a Innate immunity
653 $a Proteasome degradation pathway
653 $a Redox signaling
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690 $a 0487
690 $a 0419
710 2 $a Weill Medical College of Cornell University. $b Pharmacology. $e degree granting institution. $3 3827180
720 1 $a Bachovchin, Daniel A. $e degree supervisor.
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791 $a Ph.D.
792 $a 2024
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