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

Cell Host Microbe. 2012 Mar 15;11(3):290-7. doi: 10.1016/j.chom.2012.01.016.


Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as with RIP3(-/-) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Glycoproteins / metabolism
  • Glycoproteins / physiology*
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / metabolism
  • Herpesviridae Infections / pathology
  • Host-Pathogen Interactions
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / virology
  • Interferon-beta / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / physiology
  • Muromegalovirus / genetics
  • Muromegalovirus / immunology
  • Muromegalovirus / physiology*
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Necrosis / metabolism
  • Necrosis / virology*
  • RNA-Binding Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Viral Load
  • Viral Proteins / genetics
  • Viral Proteins / metabolism


  • Glycoproteins
  • Multiprotein Complexes
  • NF-kappa B
  • RNA-Binding Proteins
  • Viral Proteins
  • Zbp1 protein, mouse
  • Interferon-beta
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse