RIP1/RIP3 binding to HSV-1 ICP6 initiates necroptosis to restrict virus propagation in mice

Cell Host Microbe. 2015 Feb 11;17(2):229-42. doi: 10.1016/j.chom.2015.01.002.


Necroptosis is a form of programmed necrosis that is mediated by signaling complexes containing the receptor-interacting protein 3 (RIP3) and RIP1 kinases. We show that RIP3 and its interaction with the herpes simplex virus type 1 (HSV-1) protein ICP6 triggers necroptosis in infected mouse cells and limits viral propagation in mice. ICP6 interacts with RIP1/RIP3 through its RHIM domain and forms dimers/oliogmers by its C-terminal R1 domain. These binding events result in RIP1-RIP3 hetero- and RIP3-RIP3 homo-interactions and subsequent necroptosis of HSV-1-infected mouse cells. However, ICP6 RHIM cannot trigger necroptosis and even inhibits TNF-induced necroptosis in human cells. As the RHIM domain in murine cytomegalovirus protein vIRA can inhibit necroptosis in both human and mouse cells, these data suggest that both viral and host RHIM sequences determine whether the virus-host RHIM interaction is pro- or anti-necroptotic and that some viruses may evolve to escape this restriction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death*
  • Cell Line
  • GTPase-Activating Proteins / metabolism*
  • Herpesvirus 1, Human / immunology*
  • Herpesvirus 1, Human / physiology
  • Host-Pathogen Interactions*
  • Humans
  • Immune Evasion
  • Mice
  • Protein Binding
  • Protein Interaction Maps*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Viral Proteins / metabolism*
  • Virus Replication


  • GTPase-Activating Proteins
  • Ralbp1 protein, mouse
  • Viral Proteins
  • herpes simplex virus type 1-protein ICP6
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse