ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death

Sannula Kesavardhana, Teneema Kuriakose, Clifford S. Guy, Parimal Samir, R. K.Subbarao Malireddi, Ashutosh Mishra, Thirumala Devi Kanneganti

Research output: Contribution to journalArticlepeer-review


Innate sensing of influenza virus infection induces activation of programmed cell death pathways. We have recently identified Z-DNA-binding protein 1 (ZBP1) as an innate sensor of influenza A virus (IAV). ZBP1-mediated IAV sensing is critical for triggering programmed cell death in the infected lungs. Surprisingly, little is known about the mechanisms regulating ZBP1 activation to induce programmed cell death. Here, we report that the sensing of IAV RNA by retinoic acid inducible gene I (RIG-I) initiates ZBP1-mediated cell death via the RIG-I-MAVS-IFN-β signaling axis. IAV infection induces ubiquitination of ZBP1, suggesting potential regulation of ZBP1 function through posttranslational modifications. We further demonstrate that ZBP1 senses viral ribonucleoprotein (vRNP) complexes of IAV to trigger cell death. These findings collectively indicate that ZBP1 activation requires RIG-I signaling, ubiquitination, and vRNP sensing to trigger activation of programmed cell death pathways during IAV infection. The mechanism of ZBP1 activation described here may have broader implications in the context of virus-induced cell death.

Original languageEnglish (US)
Pages (from-to)2217-2229
Number of pages13
JournalJournal of Experimental Medicine
Issue number8
StatePublished - Aug 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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