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DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine

Jason W Upton1, William J Kaiser, Edward S Mocarski

  • 1Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.

Cell Host & Microbe
|March 20, 2012
PubMed

Insights

DNA-dependent activator of interferon regulatory factors (DAI) partners with Receptor-interacting protein kinase 3 (RIPK3) to trigger programmed necrosis against viral infections. This DAI-RIPK3 complex is the target of viral inhibitors, revealing a new host defense mechanism.

Area of Science:

  • Immunology
  • Cellular Biology
  • Virology

Background:

  • Programmed necrosis is a host defense mechanism eliminating infected cells.
  • Receptor-interacting protein kinase 3 (RIPK3) mediates programmed necrosis, which can be suppressed by viral inhibitors like MCMV's vIRA.

Purpose of the Study:

  • To investigate the role of DNA-dependent activator of interferon regulatory factors (DAI) in virus-induced programmed necrosis.
  • To identify the viral target of the MCMV-encoded viral inhibitor of RIP activation (vIRA).

Main Methods:

  • Assessing the effect of DAI expression and knockout on virus-induced necrosis.
  • Analyzing the impact of DAI deficiency on MCMV pathogenesis in mice.

Main Results:

  • DAI sensitizes cells to virus-induced necrosis; DAI-deficient cells are resistant.
  • DAI interacts with RIPK3 to mediate virus-induced necrosis.
  • DAI deficiency restores pathogenesis of vIRA mutant MCMV in mice, indicating DAI-RIPK3 is the vIRA target.

Conclusions:

  • DAI acts as the RIPK3 partner in mediating virus-induced programmed necrosis.
  • The DAI-RIPK3 complex is identified as the natural target of vIRA, a viral inhibitor.

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