Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

被引:80
作者
Li, Xiang [1 ,2 ,3 ,4 ]
Zhang, Peipei [3 ,4 ]
Yin, Zhiyong [1 ,2 ]
Xu, Fei [1 ,2 ]
Yang, Zhang-Hua [3 ,4 ]
Jin, Jun [1 ,2 ]
Qu, Jing [1 ,2 ]
Liu, Zhilong [1 ,2 ]
Qi, Hong [5 ]
Yao, Chenggui [6 ]
Shuai, Jianwei [1 ,2 ,3 ,4 ,7 ,8 ]
机构
[1] Xiamen Univ, Dept Phys, Xiamen 361005, Peoples R China
[2] Xiamen Univ, Fujian Prov Key Lab Soft Funct Mat Res, Xiamen 361005, Peoples R China
[3] Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, Natl Inst Data Sci Hlth & Med, Xiamen 361102, Peoples R China
[4] Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China
[5] Shanxi Univ, Complex Syst Res Ctr, Taiyuan 030006, Shanxi, Peoples R China
[6] Jiaxing Univ, Coll Data Sci, Jiaxing 314000, Peoples R China
[7] Univ Chinese Acad Sci, Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Wenzhou 325001, Zhejiang, Peoples R China
[8] Univ Chinese Acad Sci, Wenzhou Inst, Wenzhou 325001, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
PYROPTOSIS; APOPTOSIS; PATHWAYS; QUANTIFICATION; ACTIVATION; INDUCTION; LANDSCAPE; CLEAVAGE; PORE;
D O I
10.34133/2022/9838341
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new "coexisting" state in single cells is proposed when GSDMD acts as the driving force of the landscape. The "seesaw model" therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.
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页数:17
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