YAP promotes the activation of NLRP3 inflammasome via blocking K27-linked polyubiquitination of NLRP3

Nat Commun. 2021 May 11;12(1):2674. doi: 10.1038/s41467-021-22987-3.

Abstract

The transcription coactivator YAP plays a vital role in Hippo pathway for organ-size control and tissue homeostasis. Recent studies have demonstrated YAP is closely related to immune disorders and inflammatory diseases, but the underlying mechanisms remain less defined. Here, we find that YAP promotes the activation of NLRP3 inflammasome, an intracellular multi-protein complex that orchestrates host immune responses to infections or sterile injuries. YAP deficiency in myeloid cells significantly attenuates LPS-induced systemic inflammation and monosodium urate (MSU) crystals-induced peritonitis. Mechanistically, YAP physically interacts with NLRP3 and maintains the stability of NLRP3 through blocking the association between NLRP3 and the E3 ligase β-TrCP1, the latter increases the proteasomal degradation of NLRP3 via K27-linked ubiquitination at lys380. Together, these findings establish a role of YAP in the activation of NLRP3 inflammasome, and provide potential therapeutic target to treat the NLRP3 inflammasome-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Polyubiquitin / metabolism*
  • RNA Interference
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Btrc protein, mouse
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Yap1 protein, mouse
  • beta-Transducin Repeat-Containing Proteins
  • Polyubiquitin
  • Ubiquitin-Protein Ligases
  • Lysine