The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING

• Published in: Immunity (Cambridge, Mass.) Vol. 41; no. 6; pp. 919 - 933
• Main Authors: Wang, Qiang, Liu, Xing, Cui, Ye, Tang, Yijun, Chen, Wei, Li, Senlin, Yu, Huansha, Pan, Youdong, Wang, Chen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-12-2014; Elsevier Limited
• Subjects: 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
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2014.11.011

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.
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•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.