On June 24th, Dr. Gu Lichuan’s lab (State Key Lab of Microbial Technology at the School of Life Sciences) published an online an research paper entitled “Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP” in Nature Structural & Molecular Biology. Their research revealed the interaction between STING and c-di-GMP, in which STING participates in the innate immune system of human beings and c-di-GMP is a kind of secondary signal molecule of bacteria.

Shang Guijun and Li Ning, the PhD students, Zhu Deyu, the lecturer, and Zhang Junbing, the master student of Shandong University are the first authors of this paper. Prof. Gu Lichuan is the corresponding author. The research was finished in Shandong University and supported by the grants from the State Key Laboratory of Microbial Technology of SDU, 863 project and National Nature Science Foundation of China.

The innate immune system constitutes the first line of defense against microbial infection and detects infections by using pattern-recognition receptors, which recognize conserved structures in microbial pathogens such as nucleic acids and switch on the production of various cytokines such as the type I interferon. A transmembrane protein called STING (the stimulator of IFN genes; also known as TMEM173, MPYS, MITA and ERIS) plays a vital role in the response to cytoplasmic dsDNA, facilitating IFN production and linking the detection of dsDNA to the TBK-IRF3 signaling axis.

Recently, it has been demonstrated that STING also functions as a direct immunosensor of cyclic dinucleotides, which is ubiquitously expressed in bacterial species but absent in higher eukaryotes. In order to clarify the mechanism for the role of STING in the type I IFN signaling pathway and the recognition of cyclic dinucleotides, Gu’s lab solved the structures of the carboxy-terminal domain (CTD) of human STING and STING CTD complex with c-di-GMP at high resolution. A simple structural mechanism of c-di-GMP binding by the STING family is highlighted in their structures. STING exits as dimer. In response to c-di-GMP binding, the β2-β3 loop undergoes a conformational rearrangement to close onto the c-di-GMP bound cleft. STING recognizes c-di-GMP mainly through hydrophobic interaction, while almost all bacteria utilize positive charges of two arginines to attract phosphate groups of c-di-GMP.

Their study provides important information into the innate immune system of human sense and defense microbial infection. They also proved that c-di-GMP can serve as good vaccine adjuvants and have important applications in clinical prospects from molecular level. Recently, the main difficulty impeding this goal is the high price of c-di-GMP, but Gu’s lab has developed an efficient technology to synthesize and purify c-di-GMP and has applied for a national patent.

Written by: Li Ning

Edited by: Lawrence Phillips, Jing Zizhao

Source: School of Life Sciences ,www.view.sdu.edu.cn