Abstract

Inflammasome activity is important for the immune response and is instrumental in numerous clinical conditions. Here we identify a mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that the function of ASC in assembling the inflammasome is controlled by its modification with SUMO (small ubiquitin-like modifier) and identify that the nuclear ZBTB16 (zinc-finger and BTB domain-containing protein 16) promotes this SUMOylation. The physiological significance of this activity is demonstrated through the reduction of acute inflammatory pathogenesis caused by a constitutive hyperactive inflammasome by ablating ZBTB16 in a mouse model of Muckle-Wells syndrome. Together our findings identify an further mechanism by which ZBTB16-dependent control of ASC SUMOylation assembles the inflammasome to promote this pro-inflammatory response.

Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).

Details

Title
Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Author
Dong, Danfeng 1 ; Du, Yuzhang 1 ; Fei, Xuefeng 1 ; Yang, Hao 1 ; Li, Xiaofang 2 ; Yang, Xiaobao 1 ; Ma, Junrui 1 ; Huang, Shu 1 ; Ma, Zhihui 1 ; Zheng, Juanjuan 1 ; Chan, David W. 3   VIAFID ORCID Logo  ; Shi, Liyun 4 ; Li, Yunqi 5 ; Irving, Aaron T. 6   VIAFID ORCID Logo  ; Yuan, Xiangliang 1 ; Liu, Xiangfan 1 ; Ni, Peihua 1 ; Hu, Yiqun 1 ; Meng, Guangxun 7   VIAFID ORCID Logo  ; Peng, Yibing 1 ; Sadler, Anthony 8 ; Xu, Dakang 1 

1  Shanghai Jiao Tong University School of Medicine, Department of Laboratory Medicine, Ruijin Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, College of Health Sciences and Technology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
2  Northwest Women’s and Children’s Hospital, Assisted Reproduction Center, Xi’an, China (GRID:grid.440257.0) (ISNI:0000 0004 1758 3118) 
3  The Chinese University of Hong Kong-Shenzhen, School of Medicine, Shenzhen, China (GRID:grid.511521.3) 
4  Nanjing University of Chinese Medicine, Department of Microbiology and Immunology, Nanjing, China (GRID:grid.410745.3) (ISNI:0000 0004 1765 1045) 
5  Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
6  Zhejiang University School of Medicine, Department of Clinical Laboratory Studies, Second Affiliated Hospital, Hangzhou, China (GRID:grid.412465.0); Zhejiang University, Centre for Infection, Immunity &Cancer, Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X) 
7  University of Chinese Academy of Sciences, The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, Shanghai, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
8  Hudson Institute of Medical Research, Centre for Innate Immunity and Infectious Diseases, Clayton, Australia (GRID:grid.452824.d) (ISNI:0000 0004 6475 2850); Monash University, Department of Molecular and Translational Science, Clayton, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857) 
Pages
8465
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-43945-1
ProQuest document ID
2904031519
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.