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Updated: Aug 15, 2025

Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages

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Palmitoylation prevents sustained inflammation by limiting NLRP3 inflammasome activation through chaperone-mediated

Liqiu Wang1, Jing Cai1, Xin Zhao1

  • 1MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences of Sun Yat-sen University, Guangzhou, Guangdong, China.

Molecular Cell
|December 31, 2022
PubMed

Insights

S-palmitoylation of NLRP3 inflammasome by zDHHC12 acts as a crucial brake, preventing excessive inflammation. This discovery reveals a new regulatory mechanism for controlling inflammatory responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • The NLRP3 inflammasome is a key intracellular sensor for danger signals and a therapeutic target for inflammatory diseases.
  • Understanding the regulation of NLRP3 inflammasome stability and activity is crucial for controlling inflammatory responses.

Purpose of the Study:

  • To investigate the mechanisms controlling NLRP3 inflammasome kinetics and activity.
  • To identify regulators of NLRP3 inflammasome stability and function.

Main Methods:

  • Utilized biochemical assays to study S-palmitoylation of NLRP3.
  • Employed mouse models with zDHHC12 deficiency to assess inflammatory responses.
  • Analyzed disease-associated NLRP3 mutations for defects in palmitoylation.

Main Results:

  • Identified S-palmitoylation as a negative regulator of NLRP3 inflammasome activation.
  • zDHHC12 was identified as the specific S-acyltransferase responsible for NLRP3 palmitoylation.
  • zDHHC12 deficiency exacerbated inflammatory symptoms and lethality in mouse models.
  • Disease-associated NLRP3 mutations impaired palmitoylation, leading to hyperactive inflammasomes.

Conclusions:

  • zDHHC12 acts as a repressor of NLRP3 inflammasome activation through promoting NLRP3 degradation via chaperone-mediated autophagy.
  • Dynamic palmitoylation of NLRP3 is a critical mechanism for controlling inflammasome activity.
  • This finding offers new insights into the regulation of inflammatory pathways and potential therapeutic strategies.
Keywords:
NLRP3chaperone-mediated autophagyinflammasomeinflammationpalmitoylation

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