
AsianScientist (Jan. 5, 2015) – Researchers have clarified the role of stimulator of interferon genes (STING) in response to pathogen double stranded DNA, showing that poly-ubiquitination by the enzyme AMRF is essential. The study, published in the journal Immunity, has been selected as the cover story of the December 18 issue.

Several host DNA-binding proteins are involved in the detection of microbial DNA in the cytoplasm, triggering a protective type I interferon response. An emerging commonality of the mechanism of action among these DNA sensors is the convergence of their signaling pathways on STING, a transmembrane protein found in the endoplasmic reticulum (ER).
Recent research has shown that foreign DNA triggers the dimerization and translocation of STING from the ER to the Golgi apparatus and subsequently to the perinuclear microsome compartment. It is also known that the TANK-binding kinase 1 (TBK1) simultaneously congregates to the same compartment in a STING-dependent manner and that the STING-TBK1 complex is required for downstream signaling. However, it is not known what drives the simultaneous translocation of STING and TBK1 and how all this membrane traffic is dynamically regulated.
Under the supervision of Professor Wang Chen from the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, researchers have uncovered new mechanistic insights into the modulation of STING-TBK1 axis during DNA virus infection.
They found ER-resident AMFR and INSIG1 complex mediated K27-linked poly-ubiquitination of STING in response to DNA-triggered anti-viral signaling. These poly-ubiquitin chains are then required for proper engagement with TBK1 and efficient downstream signaling transduction. Mice deficient in INSIG1 specifically in myeloid cells were more susceptible to herpes simplex virus 1 infection, suggesting the importance of this poly-ubiquitination pathway in response to double stranded DNA viruses.
This work highlights the key role of ER membrane proteins AMFR and INSIG1 as well as K27-linked poly-ubiquitin chains in STING-mediated signaling, revealing an important missing link in the STING signaling pathway.
The article can be found at: Wang et al. (2014) The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING.
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Source: Chinese Academy of Sciences.
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