The PGAM5–NEK7 interaction is a therapeutic target for NLRP3 inflammasome activation in colitis
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 <i>via</i> 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.
Authors
- Feng Zhao (ORCID: https://orcid.org/0000-0002-7959-0394)
- Lei Shi (ORCID: https://orcid.org/0000-0003-1679-3618)
- Gang Xu (ORCID: https://orcid.org/0000-0003-4974-9496)
- Jiayang Wu (ORCID: https://orcid.org/0000-0003-2900-7399)
- Xudong Wu (ORCID: https://orcid.org/0000-0003-2260-035X)
- Qinghong Shang (ORCID: https://orcid.org/0009-0007-3255-0399)
- Dalei Wu (ORCID: https://orcid.org/0000-0003-1817-7229)
- Tao Pang (ORCID: https://orcid.org/0000-0001-5420-2060)
- Jin-Qian Song
- Chenglong Gao (ORCID: https://orcid.org/0000-0001-6594-0114)
- Xindong Liu (ORCID: https://orcid.org/0000-0002-2465-0337)
- Xin Guan (ORCID: https://orcid.org/0000-0002-9129-327X)
- Haojie Wang (ORCID: https://orcid.org/0009-0002-3260-811X)
- Y X Zheng (ORCID: https://orcid.org/0009-0003-2808-551X)
Institutions
- Army Medical University (CN)
- Shandong University (CN)
- China Pharmaceutical University (CN)
- Dalian Medical University (CN)
- Southwest Hospital (CN)
- State Key Laboratory of Microbial Technology
- State Key Laboratory of Natural Medicine
- Southeast University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1016/j.apsb.2024.11.019
- Citations
- 3
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- National Natural Science Foundation of China
- China Pharmaceutical University
- Nanjing University
- State Key Laboratory of Pharmaceutical Biotechnology