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Palmitoylation facilitates inflammation through suppressing NOD2 degradation mediated by the selective autophagy

Lingli Zhou1, Huasong Zeng2, Jun Cui1

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

Autophagy
|March 21, 2022
PubMed

Insights

Palmitoylation stabilizes NOD2, a key immune sensor, by preventing its degradation. A NOD2 variant linked to autoinflammatory disease shows increased palmitoylation and inflammation due to impaired degradation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • NOD2 is an intracellular pattern recognition receptor sensing bacterial peptidoglycan, crucial for inflammatory and antimicrobial responses.
  • Dysregulated NOD2 signaling is implicated in various immune and inflammatory diseases.
  • Palmitoylation of NOD2 is essential for its membrane localization and activation, but its role in NOD2 stability and inflammation is not fully understood.

Purpose of the Study:

  • To investigate the role of S-palmitoylation in regulating NOD2 stability and its impact on inflammation.
  • To identify mechanisms by which NOD2 variants contribute to autoinflammatory diseases.

Main Methods:

  • Investigated the interplay between NOD2 S-palmitoylation and autophagic degradation pathways.
  • Identified and characterized a gain-of-function NOD2 variant (NOD2sR444C) associated with autoinflammatory disease.

Main Results:

  • S-palmitoylation was found to restrict the autophagic degradation of NOD2, mediated by SQSTM1.
  • A gain-of-function NOD2 short isoform variant (NOD2sR444C) was identified in patients with autoinflammatory disease.
  • This variant exhibits increased S-palmitoylation and reduced autophagic degradation, leading to excessive inflammation.

Conclusions:

  • S-palmitoylation acts as a critical regulator of NOD2 stability by inhibiting its autophagic clearance.
  • The NOD2sR444C variant exemplifies how altered palmitoylation and impaired degradation can drive autoinflammatory conditions.
Keywords:
InflammationNOD2S-palmitoylationSQSTM1selective autophagy

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