PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner

Autophagy. 2017 Sep 2;13(9):1590-1601. doi: 10.1080/15548627.2017.1341453. Epub 2017 Aug 8.

Abstract

A variant within the gene locus encoding PTPN22 (protein tyrosine phosphatase, non-receptor type 22) emerged as an important risk factor for auto-inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, but at the same time protects from Crohn disease, one of the 2 main forms of inflammatory bowel diseases. We have previously shown that loss of PTPN22 results in decreased NLRP3 (NLR family pyrin domain containing 3) activation and that this effect is mediated via enhanced NLRP3 phosphorylation. However, it is unclear how phosphorylation of NLRP3 mediates its inhibition. Here, we demonstrate that loss of macroautophagy/autophagy abrogates the inhibitory effect on NLRP3 activation observed upon loss of PTPN22. Phosphorylated, but not nonphosphorylated NLRP3 is found in autophagosomes, indicating that NLRP3 phosphorylation mediates its inactivation via promoting sequestration into phagophores, the precursors to autophagosomes. This finding shows that autophagy and NLRP3 inflammasome activation are connected, and that PTPN22 plays a key role in the regulation of those 2 pathways. Given its role in inflammatory disorders, PTPN22 might be an attractive therapeutic target, and understanding the cellular mechanisms modulated by PTPN22 is of crucial importance.

Keywords: Lyp; NLRP3; NOD-like receptor protein; PEST-enriched phosphatase; SQSTM1; inflammasome; tyrosine phosphorylation.

MeSH terms

  • Animals
  • Autophagosomes / metabolism
  • Autophagy*
  • Autophagy-Related Proteins
  • CARD Signaling Adaptor Proteins / metabolism
  • Carrier Proteins / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1beta / metabolism*
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / metabolism*
  • Sequestosome-1 Protein / metabolism

Substances

  • Atg16l1 protein, mouse
  • Autophagy-Related Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pycard protein, mouse
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22