The PGAM5-NEK7 interaction is a therapeutic target for NLRP3 inflammasome activation in colitis.
10.1016/j.apsb.2024.11.019
- Author:
Cheng-Long GAO
1
;
Jinqian SONG
1
;
Haojie WANG
1
;
Qinghong SHANG
2
;
Xin GUAN
1
;
Gang XU
3
;
Jiayang WU
1
;
Dalei WU
2
;
Yueqin ZHENG
1
;
Xudong WU
4
;
Feng ZHAO
5
;
Xindong LIU
6
;
Lei SHI
5
;
Tao PANG
1
Author Information
1. State Key Laboratory of Natural Medicines, New Drug Screening Center, Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China.
2. Helmholtz International Laboratory, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
3. Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
4. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
5. College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
6. Institute of Pathology & Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
- Publication Type:Journal Article
- Keywords:
APEX2 proximity labeling;
Colitis;
Macrophage;
NEK7;
NLRP3 inflammasome;
PGAM5;
Protein–protein interaction;
Punicalagin
- From:
Acta Pharmaceutica Sinica B
2025;15(1):349-370
- CountryChina
- Language:English
-
Abstract:
The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5-NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5-NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5-NEK7 interaction.
