The PGAM5–NEK7 interaction is a therapeutic target for NLRP3 inflammasome activation in colitis

Bibliographic Details
Title: The PGAM5–NEK7 interaction is a therapeutic target for NLRP3 inflammasome activation in colitis
Authors: Cheng-Long Gao, Jinqian Song, Haojie Wang, Qinghong Shang, Xin Guan, Gang Xu, Jiayang Wu, Dalei Wu, Yueqin Zheng, Xudong Wu, Feng Zhao, Xindong Liu, Lei Shi, Tao Pang
Source: Acta Pharmaceutica Sinica B, Vol 15, Iss 1, Pp 349-370 (2025)
Publisher Information: Elsevier, 2025.
Publication Year: 2025
Collection: LCC:Therapeutics. Pharmacology
Subject Terms: PGAM5, APEX2 proximity labeling, Protein–protein interaction, NEK7, NLRP3 inflammasome, Punicalagin, Therapeutics. Pharmacology, RM1-950
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2211-3835
Relation: http://www.sciencedirect.com/science/article/pii/S2211383524004520; https://doaj.org/toc/2211-3835
DOI: 10.1016/j.apsb.2024.11.019
Access URL: https://doaj.org/article/ce702fa6522f4d1491802f4ebbef6ffc
Accession Number: edsdoj.702fa6522f4d1491802f4ebbef6ffc
Database: Directory of Open Access Journals
More Details
ISSN:22113835
DOI:10.1016/j.apsb.2024.11.019
Published in:Acta Pharmaceutica Sinica B
Language:English