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DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death

Roshan J Thapa1, Justin P Ingram1, Katherine B Ragan2

  • 1Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Cell Host & Microbe
|October 18, 2016
PubMed

Insights

DAI (ZBP1/DLM-1) is identified as a crucial sensor for Influenza A virus (IAV) RNA, activating RIPK3 kinase. This activation triggers cell death pathways, and DAI-deficient mice show lethal IAV infections.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Influenza A virus (IAV) causes cytotoxicity by activating host kinase RIPK3.
  • RIPK3 mediates cell death through necroptosis (MLKL-dependent) and apoptosis (RIPK1 and FADD-dependent).
  • The mechanism by which IAV activates RIPK3 is currently unknown.

Purpose of the Study:

  • To elucidate the mechanism of RIPK3 activation by IAV.
  • To identify the host factors involved in sensing IAV and triggering cell death pathways.

Main Methods:

  • Utilized cell-based assays to investigate DAI's role in IAV infection.
  • Employed genetic approaches using DAI-deficient cells and mutant DAI.
  • Conducted experiments with DAI-deficient mice to assess in vivo IAV control.

Main Results:

  • DAI (ZBP1/DLM-1), a known DNA sensor, is essential for RIPK3 activation by IAV.
  • DAI directly recognizes IAV genomic RNA and binds to RIPK3.
  • DAI is required for the recruitment of MLKL and RIPK1 to RIPK3, initiating cell death.
  • Cells lacking functional DAI are resistant to IAV-induced necroptosis and apoptosis.
  • DAI-deficient mice exhibit uncontrolled IAV replication and lethal respiratory disease.

Conclusions:

  • DAI acts as a critical sensor linking IAV replication to RIPK3 activation.
  • DAI is implicated as a sensor for RNA viruses, not just DNA.
  • DAI is essential for host defense against IAV infection through the induction of cell death.

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