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NEK7 Cys298 is important for NLRP3 inflammasome and targetable by dimethyl fumarate
Yandong Zhang1, Helena Lindner2, Brian So2
1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA; Department of Medicine and Department of Chemistry, University of Chicago, Chicago, IL, USA.
Abstract:
Dimethyl fumarate (DMF), a cysteine targeting agent, is clinically used to treat multiple sclerosis and psoriasis. However, its precise molecular mechanism remains incompletely understood. Here, we investigated the effects of DMF on NLRP3 inflammasome activation. DMF suppresses NLRP3 inflammasome activity at both the priming and activation steps. Using chemoproteomics, we identified DMF targets in macrophages, including IRAK3/4 and RELA/B involved in the NLRP3 priming step, NEK7 involved in NLRP3 early activation, and GSDMD involved in NLRP3 late activation. To understand how DMF inhibits NLRP3 early activation, we showed that DMF modifies NEK7 Cys298 to disrupt NLRP3-NEK7 interaction and inflammasome activation. Interestingly, NEK7 Cys298 is critical for NLRP3 inflammasome activation. This study provides mechanistic insights into DMF's immunomodulatory effects and suggests that targeting NEK7 Cys298 can be a novel strategy for inflammatory diseases. Our work highlights the utility of DMF to identify functionally important cysteine residues in immune signaling pathways.
Insights
Dimethyl fumarate (DMF) suppresses NLRP3 inflammasome activation by targeting key proteins like NEK7. Modifying NEK7 Cys298 disrupts inflammasome function, offering new therapeutic strategies for inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Dimethyl fumarate (DMF) is a drug used for multiple sclerosis and psoriasis, but its exact mechanism is unclear.
- The NLRP3 inflammasome is a key regulator of inflammation.
Purpose of the Study:
- To investigate the effects of DMF on NLRP3 inflammasome activation.
- To identify the molecular targets of DMF in the NLRP3 inflammasome pathway.
Main Methods:
- Chemoproteomics was used to identify DMF targets in macrophages.
- Experiments were conducted to assess DMF's impact on NLRP3 inflammasome priming and activation steps.
- The interaction between DMF, NEK7, and NLRP3 was analyzed.
Main Results:
- DMF inhibits NLRP3 inflammasome activation at both priming and activation stages.
- DMF targets include IRAK3/4, RELA/B, NEK7, and GSDMD.
- DMF modifies NEK7 at Cys298, disrupting the NLRP3-NEK7 interaction and inflammasome assembly.
Conclusions:
- DMF's immunomodulatory effects are partly mediated by inhibiting NLRP3 inflammasome activation.
- Targeting NEK7 Cys298 represents a potential therapeutic strategy for inflammatory conditions.
- DMF serves as a valuable tool for discovering functionally critical cysteine residues in immune signaling.
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