The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING

Immunity. 2014 Dec 18;41(6):919-33. doi: 10.1016/j.immuni.2014.11.011. Epub 2014 Nov 28.

Abstract

Stimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin-induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK-binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1(-/-) mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Activation / genetics
  • Herpes Simplex / immunology*
  • Herpesvirus 1, Human / immunology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microsomes / metabolism*
  • Myeloid Cells / physiology*
  • Myeloid Cells / virology
  • Protein Binding / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport / genetics
  • Receptors, Autocrine Motility Factor / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / genetics

Substances

  • INSIG1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • STING1 protein, human
  • AMFR protein, human
  • Receptors, Autocrine Motility Factor
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human