A stimulator of interferon genes (STING), also known as MITA, ERIS, MPYS and TMEM173, is an essential signaling molecule for DNA and cyclic di-GMP (c-di-GMP)-mediated type I interferon (IFN) production via TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway. It contains an N-terminal transmembrane region and a cytosolic C-terminal domain (CTD). The membrane protein STING was initially characterized as a plasma membrane tetraspanner associated with type II major histocompatibility complex (MHC-II) with a function to transduce apoptotic signals during antigen presentation. STING was shown to reside predominantly in the endoplasmic reticulum (ER) membrane, where it plays a role in relaying the intracellular DNA-mediated innate signals to type I IFN (IFN-I) production. STING-deficient (Tmem173？/？) cells are defective in IFN-I induction triggered by viral, bacterial, or synthetic DNA and STING-deficient mice are more sensitive than wild-type (WT) controls when infected with DNA viruses such as HSV-1.

Despite the essential role of STING in DNA-mediated IFN-I induction, the mechanisms of its action are less clear and controversial in some cases. In a recent study published in Immunity (Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding, Immunity. 10 May 2012), Professor LIU Zhi-Jie at the Institute of Biophysics, Chinese Academy of Sciences and his colleagues describe the crystal structures of the STING CTD alone and in a complex with c-di-GMP refined to 2.45 angstrom and 2.15 angstrom resolution, respectively. The structural, functional, and mutagenesis data unravel several hitherto unknown aspects of STING and shed light on its mechanism of activation. STING forms homotypic interactions that are essential for stimulation of IFN production. The structures of STING CTD provide detailed molecular insights into the nature of this homotypic architecture. Notably, the structure of STING CTD is very different from any known structure of adaptors or proteins functioning in innate immune responses and therefore STING may represent a novel class of sensors involved in detection of bacterial intrusion. The protein expression, analytical, and structural evidences revealed that the aa 153–173 region was not a transmembrane region as predicted previously but is a hydrophobic dimer interface. The structure of the binary complex maps the exact location of the c-di-GMP binding site on STING and unveils a unique mode of binding of c-di-GMP to proteins. Structure-guided mutagenesis studies showed that STING exists and functions as a dimer.

In a finding contrary to previous reports, the authors show that ubiquitination of K150 may not be a prerequisite for dimerization. The c-di-GMP binding pocket is formed via dimerization of STING. Interestingly, binding of c-di-GMP enhances the association of TBK1 with STING. Although the results further our understanding of the nature of the homotypic interactions of STING essential for stimulation of IFN production, questions on how the signal of intrusion sensed by STING is relayed, leading to recruitment of downstream effector molecules, remain to be investigated.

This work was supported by grants from the Ministry of Science and Technology of China, the Natural Science Foundation of China and Chinese Academy of Sciences.

(http://www.cell.com/immunity/abstract/S1074-7613(12)00178-1)

Figure legend: STING dimer in cyclic di-GMP-mediated signaling pathway.(From LIU Zhi-Jie et.al)