- Pingwei Li
- ILSB / Room 2157
- Graduate Education
- Ph.D. Peking University (1996)
- Postdoc. Fred Hutchinson Cancer Research Center (1998-2001)
- Postdoc. California Institute of Technology (2003-2005)
- Joined Texas A&M in 2005
Structural Biology and Innate Immunity
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-β 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 IκB 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.
Our comprehensive structural and functional studies provided critical insights into the mechanisms of DNA sensing through the cGAS/STING pathway. However, the detailed mechanisms of how cytosolic DNA mediates the induction of IFNs are still not fully understood. For example, it is not clear how cGAMP binding by STING initiates the signaling cascade. It is also not clear how the cGAS/STING pathway is regulated at molecular level. The current research in my lab aims to understand how cGAMP activates STING mediated signaling. We use biochemical, biophysical, structural, and cellular approaches to elucidate the molecular mechanisms of innate immunity towards microbial nucleic acids. In addition, we are also interested in studying other signaling pathways that are important in innate immunity.
Zhou, X, Yu, J, Cheng, X, Zhao, B, Manyam, GC, Zhang, L et al.. The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming. Nat. Immunol. 2019; :.
Zhao, B, Du, F, Xu, P, Shu, C, Sankaran, B, Bell, SL et al.. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature. 2019;569 (7758):718-722.
Li, X, Deng, M, Petrucelli, AS, Zhu, C, Mo, J, Zhang, L et al.. Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon. Immunity. 2019;50 (3):591-599.e6.
Ghosh, A, Shao, L, Sampath, P, Zhao, B, Patel, NV, Zhu, J et al.. Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production. Immunity. 2019;50 (1):51-63.e5.
Xie, X, Jin, J, Zhu, L, Jie, Z, Li, Y, Zhao, B et al.. Cell type-specific function of TRAF2 and TRAF3 in regulating type I IFN induction. Cell Biosci. 2019;9 :5.
Lahaye, X, Gentili, M, Silvin, A, Conrad, C, Picard, L, Jouve, M et al.. NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation. Cell. 2018;175 (2):488-501.e22.
Patrick, KL, Wojcechowskyj, JA, Bell, SL, Riba, MN, Jing, T, Talmage, S et al.. Quantitative Yeast Genetic Interaction Profiling of Bacterial Effector Proteins Uncovers a Role for the Human Retromer in Salmonella Infection. Cell Syst. 2018;7 (3):323-338.e6.
Wang, Z, Ma, Z, Castillo-González, C, Sun, D, Li, Y, Yu, B et al.. SWI2/SNF2 ATPase CHR2 remodels pri-miRNAs via Serrate to impede miRNA production. Nature. 2018;557 (7706):516-521.
Yang, Y, Shu, C, Li, P, Igumenova, TI. Structural Basis of Protein Kinase Cα Regulation by the C-Terminal Tail. Biophys. J. 2018;114 (7):1590-1603.
Shen, Q, Shi, J, Zeng, D, Zhao, B, Li, P, Hwang, W et al.. Molecular Mechanisms of Tight Binding through Fuzzy Interactions. Biophys. J. 2018;114 (6):1313-1320.