The research in my lab focuses on elucidating the structural basis of innate immune responses towards microbial nucleic acids. The cGAS/STING pathway plays a central role in innate immunity toward bacterial and viral DNA. cGAS is activated by dsDNA and catalyzes the synthesis of a cyclic dinucleotide cGAMP, which binds to the adaptor STING that mediates the recruitment and activation of protein kinase TBK1 and transcription factor IRF-3. Activated IRF-3 translocates to the nucleus and induces the expression of type I interferons (IFN), an important family of antiviral cytokine. To elucidate the mechanism of cGAS activation, we determined the structures of cGAS in isolation and in complex with DNA. The cGAS/DNA complex structure reveals that cGAS interacts with DNA through two binding sites. Enzyme assays and IFN-? reporter assays of cGAS mutants demonstrate that interactions at both DNA binding sites are essential for cGAS activation. To investigate how cGAMP activates STING, we determined the structures of STING in isolation and in complex with cGAMP. These structures reveal that STING forms a V-shaped dimer and binds cGAMP at the dimer interface. We have also determined the structures of TBK1 in complex with two inhibitors, which show that TBK1 exhibits an I?B kinase fold with distinct domain arrangement. To elucidate the mechanism of IRF-3 recruitment by STING, we determined the structure of a phosphorylated STING peptide bound to IRF-3. To understand how phosphorylation activates IRF-3, we solved the structure of an IRF-3 phosphomimetic mutant bound to CBP, which reveals how phosphorylation induces the dimerization and activation of IRF-3.
- Ghosh, A., Shao, L., Sampath, P., Zhao, B., Patel, N. V., Zhu, J., ... Sarkar, S. N. (2019). Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production. IMMUNITY. 50(1), 51-+.
- Lahaye, X., Gentili, M., Silvin, A., Conrad, C., Picard, L., Jouve, M., ... Manel, N. (2018). NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation.. CELL. 175(2), 488-501.e22.
- Patrick, K. L., Wojcechowskyj, J. A., Bell, S. L., Riba, M. N., Jing, T., Talmage, S., ... Watson, R. O. (2018). Quantitative Yeast Genetic Interaction Profiling of Bacterial Effector Proteins Uncovers a Role for the Human Retromer in Salmonella Infection. Cell systems. 7(3), 323-338.e6.
- Wang, Z., Ma, Z., Castillo-Gonzalez, C., Sun, D. i., Li, Y., Yu, B., ... Zhang, X. (2018). SWI2/SNF2 ATPase CHR2 remodels pri-miRNAs via Serrate to impede miRNA production. NATURE. 557(7706), 516-+.
- Yang, Y., Shu, C., Li, P., & Igumenova, T. I. (2018). Structural Basis of Protein Kinase C alpha Regulation by the C-Terminal Tail. Biophys J. 114(7), 1590-1603.