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

Cheng-Long Gao1,2, Jinqian Song1, Haojie Wang1

  • 1State 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.

Acta Pharmaceutica Sinica. B
|March 5, 2025
PubMed

Insights

Mice lacking PGAM5 show reduced ulcerative colitis severity by suppressing NLRP3 inflammasome activation. The PGAM5-NEK7 interaction drives inflammasome activation, offering a therapeutic target for colitis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Gastroenterology

Background:

  • Overactivation of the NLRP3 inflammasome is implicated in ulcerative colitis pathogenesis.
  • PGAM5, a mitochondrial phosphatase, influences NLRP3 inflammasome activation in macrophages, but its specific role in ulcerative colitis and regulatory mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of PGAM5 in ulcerative colitis.
  • To elucidate the mechanisms by which PGAM5 regulates NLRP3 inflammasome activity.
  • To identify potential therapeutic strategies targeting the PGAM5-NLRP3 inflammasome axis.

Main Methods:

  • Utilized dextran sodium sulfate (DSS)-induced mouse model of colitis.
  • Employed APEX2-based proximity labeling coupled with quantitative proteomics to identify PGAM5 binding partners.
  • Investigated the effect of punicalagin on PGAM5-NEK7 interaction and NLRP3 inflammasome activation in macrophages.

Main Results:

  • PGAM5 deficiency ameliorated DSS-induced colitis in mice by suppressing NLRP3 inflammasome activation.
  • NEK7 was identified as a novel binding partner of PGAM5, promoting NLRP3 inflammasome assembly and activation independently of PGAM5 phosphatase activity.
  • Punicalagin disrupted the PGAM5-NEK7 interaction, inhibiting NLRP3 inflammasome activation and reducing colitis severity in mice.

Conclusions:

  • The PGAM5-NEK7 interaction is crucial for NLRP3 inflammasome activation in macrophages.
  • Targeting the PGAM5-NEK7 interaction presents a promising therapeutic strategy for ulcerative colitis.
  • PGAM5 plays a significant role in the pathogenesis of ulcerative colitis through its interaction with NEK7 and NLRP3 inflammasome activation.
Keywords:
APEX2 proximity labelingColitisMacrophageNEK7NLRP3 inflammasomePGAM5Protein–protein interactionPunicalagin

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