Immunity (Cambridge, Mass.), 2014-12, Vol.41 (6), p.919-933
2014
Details
- Autor(en) / Beteiligte
- Titel
- The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING
- Ist Teil von
- Immunity (Cambridge, Mass.), 2014-12, Vol.41 (6), p.919-933
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •STING signaling is drastically abolished in Amfr−/− cells•AMFR catalyzes K27-linked polyubiquitination of STING, which depends on INSIG1•The K27-linked polyubiquitin on STING facilitates TBK1 recruitment and activation•Myeloid-cell-specific Insig1−/− mice are more susceptible to HSV-1 infection STING is essential for host immune responses triggered by microbial DNAs. How STING relays activating signaling to the downstream kinase TBK1 remains unknown. Wang et al. demonstrate that ER-resident ubiquitin ligase AMFR catalyzes K27-linked polyubiquitination of STING, which creates an anchoring platform for recruiting and activating TBK1.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613eISSN: 1097-4180DOI: 10.1016/j.immuni.2014.11.011Titel-ID: cdi_proquest_miscellaneous_1647015704
- Format
- –
- Schlagworte
- Animals, Cells, Cultured, Deoxyribonucleic acid, DNA, Endoplasmic Reticulum - metabolism, Enzyme Activation - genetics, Herpes Simplex - immunology, Herpes simplex virus 1, Herpesvirus 1, Human - immunology, Infections, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - metabolism, Kinases, Membrane Proteins - genetics, Membrane Proteins - metabolism, Mice, Mice, Inbred Strains, Mice, Knockout, Microsomes - metabolism, Motility, Myeloid Cells - physiology, Myeloid Cells - virology, Protein Binding - genetics, Protein Transport - genetics, Protein-Serine-Threonine Kinases - metabolism, Proteins, Receptors, Autocrine Motility Factor - metabolism, Sensors, Signal Transduction, Ubiquitin-Protein Ligases - metabolism, Ubiquitination - genetics