Stimulator of interferon genes (STING, a.k.a MITA, ERIS or MPYS) is a central component in innate immunity against DNA virus. A research team led by Prof. WANG Chen at the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences, CAS, demonstrated that K27-linked poly-ubiquitination of STING catalyzed by the ER-associated E3 ligase AMFR is essential for STING-mediated signaling and innate antiviral response.
Recent breakthroughs have uncovered several potential DNA-binding proteins to sense the presence of microbial DNAs in the cytoplasm, and consequently to induce the type I interferon production. An emerging theme of the action of these DNA sensors is that, signaling pathways initiating from them are apparently converged on STING, a transmembrane protein in the endoplasmic reticulum (ER). It is recently observed that cytosolic exogenous DNA triggers STING to rapidly dimerize and translocate from ER, through the Golgi apparatus, and to the perinuclear microsome compartment. The TANK-binding kinase 1 (TBK1) congregates simultaneously to the same compartment in a STING-dependent manner. Notably, the DNA-driven assembly of STING-TBK1 complex is required for TBK1 activation, which subsequently activates the transcriptional factor IRF3. It remains to be elucidated what drives the simultaneous translocation of STING and TBK1, and how this membrane traffic is dynamically modulated.
Under the supervision of Prof. WANG Chen from SIBCB, WANG Qiang, LIU Xing and their colleagues identified AMFR and INSIG1 as dynamic and essential component of STING protein complex. INSIG1 recruited AMFR to catalyze K27-linked polyubiquitination of STING upon microbial DNA challenge. The ubiquitin chains created 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-cells-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.
This work entitled “The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING” was published as a cover story and highlighted by SHU Hongbing and WANG Yanyi with a title of “Adding to the STING” on December 18th, 2014, IMMUNITY. It was supported by grants from the Ministry of Science and Technology of China, National Natural Science Foundation of China, and the China Postdoctoral Research Program.
CONTACT:
WANG Chen, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China.
Email: cwang01@sibcb.ac.cn
Fig1.Upon microbial DNA sensing, the ER ubiquitin ligase AMFR and INSIG1 catalyze the K27-linked poly-ubiquitination of STING, thus creating an anchoring platform for recruiting TBK1 and resulting in the translocation and co-aggregation of TBK1 with STING in the perinuclear microsomes. Insights gained in this study are highlighted by the colored diagram.
Fig2. This work was selected as a cover story of Immunity of December 18,2014
(Images provided by Prof. WANG Chen`s group)
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