iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING

Nat Immunol. 2016 Sep;17(9):1057-66. doi: 10.1038/ni.3510. Epub 2016 Jul 18.

Abstract

STING is a central adaptor in the innate immune response to DNA viruses. However, the manner in which STING activity is regulated remains unclear. We identified iRhom2 ('inactive rhomboid protein 2') as a positive regulator of DNA-virus-triggered induction of type I interferons. iRhom2 deficiency markedly impaired DNA-virus- and intracellular-DNA-induced signaling in cells, and iRhom2-deficient mice were more susceptible to lethal herpes simplex virus type 1 (HSV-1) infection. iRhom2 was constitutively associated with STING and acted in two distinct processes to regulate STING activity. iRhom2 recruited the translocon-associated protein TRAPβ to the STING complex to facilitate trafficking of STING from the endoplasmic reticulum to perinuclear microsomes. iRhom2 also recruited the deubiquitination enzyme EIF3S5 to maintain the stability of STING through removal of its K48-linked polyubiquitin chains. These results suggest that iRhom2 is essential for STING activity, as it regulates TRAPβ-mediated translocation and EIF3S5-mediated deubiquitination of STING.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Eukaryotic Initiation Factor-3 / metabolism
  • Herpes Simplex / immunology*
  • Herpesvirus 1, Human / immunology*
  • Immunity, Innate
  • Interferon Type I / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes / metabolism*
  • Protein Binding
  • Protein Stability
  • Protein Transport / genetics
  • Tartrate-Resistant Acid Phosphatase / metabolism
  • Ubiquitination

Substances

  • Carrier Proteins
  • Eukaryotic Initiation Factor-3
  • Interferon Type I
  • MPYS protein, mouse
  • Membrane Proteins
  • iRhom2 protein, mouse
  • Acp5 protein, mouse
  • Tartrate-Resistant Acid Phosphatase