EphA2 phosphorylates NLRP3 and inhibits inflammasomes in airway epithelial cells

Ao Zhang, Junji Xing, Tianliang Xia, Hua Zhang, Mingli Fang, Shibing Li, Yong Du, Xian C Li, Zhiqiang Zhang, Mu-Sheng Zeng

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Inflammasomes are intracellular complexes that form in the cytosol of inflammatory cells. NLRP3 is one of the sensor proteins in the complex that can recognize a wide variety of stimuli ranging from microbial components to environmental particulates. Here, we report that in mouse airway epithelial cells (AECs), inflammasome activation is inhibited by EphA2, a member of the transmembrane tyrosine kinase receptor family, via tyrosine phosphorylation of NLRP3 in a model of reovirus infection. We find that EphA2 depletion markedly enhances interleukin-1β (IL-1β) and interleukin-18 (IL-18) production in response to the virus. EphA2-/- mice show stronger inflammatory infiltration and enhanced inflammasome activation upon viral infection, and aggravated asthma symptoms upon ovalbumin (ova) induction. Mechanistically, EphA2 binds to NLRP3 and induces its phosphorylation at Tyr132, thereby interfering with ASC speck formation and blocking the activation of the NLRP3-inflammasome. These data demonstrate that reovirus employs EphA2 to suppress inflammasome activation in AECs and that EphA2 deficiency causes a pathological exacerbation of asthma in an ova-induced asthma model.

Original languageEnglish (US)
Article numbere49666
Pages (from-to)e49666
JournalEMBO Reports
Volume21
Issue number7
Early online dateApr 30 2020
DOIs
StatePublished - Jul 3 2020

Keywords

  • EphA2
  • NLRP3
  • asthma
  • inflammasome
  • reovirus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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