Palmitoylation of NOD1 and NOD2 Is Required for Bacterial Sensing

Science. 2019 Oct 25;366(6464):460-467. doi: 10.1126/science.aau6391. Epub 2019 Oct 24.

Abstract

The nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2) are intracellular pattern-recognition proteins that activate immune signaling pathways in response to peptidoglycans associated with microorganisms. Recruitment to bacteria-containing endosomes and other intracellular membranes is required for NOD1/2 signaling, and NOD1/2 mutations that disrupt membrane localization are associated with inflammatory bowel disease and other inflammatory conditions. However, little is known about this recruitment process. We found that NOD1/2 S-palmitoylation is required for membrane recruitment and immune signaling. ZDHHC5 was identified as the palmitoyltransferase responsible for this critical posttranslational modification, and several disease-associated mutations in NOD2 were found to be associated with defective S-palmitoylation. Thus, ZDHHC5-mediated S-palmitoylation of NOD1/2 is critical for their ability to respond to peptidoglycans and to mount an effective immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / metabolism*
  • Animals
  • Cysteine / chemistry
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Lipoylation*
  • Macrophages / immunology
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nod1 Signaling Adaptor Protein / chemistry*
  • Nod2 Signaling Adaptor Protein / chemistry*
  • Peptidoglycan
  • Phagosomes / immunology
  • Phagosomes / microbiology
  • Protein Processing, Post-Translational
  • RAW 264.7 Cells
  • Salmonella typhimurium
  • Signal Transduction*

Substances

  • NOD1 protein, human
  • NOD2 protein, human
  • Nod1 Signaling Adaptor Protein
  • Nod2 Signaling Adaptor Protein
  • Peptidoglycan
  • Acyltransferases
  • ZDHHC5 protein, human
  • Cysteine

Grant support