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Pingwei Li

Li, Pingwei
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.

Recent Publications

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  1. Hoffpauir, CT, Bell, SL, West, KO, Jing, T, Wagner, AR, Torres-Odio, S et al.. TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection. J. Immunol. 2020; :.
    doi: 10.4049/jimmunol.1901511. PubMed PMID:32404352. .

  2. Cho, JH, Zhao, B, Shi, J, Savage, N, Shen, Q, Byrnes, J et al.. Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses. Proc. Natl. Acad. Sci. U.S.A. 2020;117 (12):6550-6558.
    doi: 10.1073/pnas.1920582117. PubMed PMID:32152123. PubMed Central PMC7104383.

  3. 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;20 (7):879-889.
    doi: 10.1038/s41590-019-0405-2. PubMed PMID:31182807. PubMed Central PMC6588407.

  4. 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.
    doi: 10.1038/s41586-019-1228-x. PubMed PMID:31118511. PubMed Central PMC6596994.

  5. 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.
    doi: 10.1016/j.immuni.2019.02.009. PubMed PMID:30893587. PubMed Central PMC6469509.

  6. 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.
    doi: 10.1016/j.immuni.2018.12.013. PubMed PMID:30635239. PubMed Central PMC6342484.

  7. 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.
    doi: 10.1186/s13578-018-0268-5. PubMed PMID:30622699. PubMed Central PMC6318904.

  8. 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.
    doi: 10.1016/j.cell.2018.08.062. PubMed PMID:30270045. .

  9. 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.
    doi: 10.1016/j.cels.2018.06.010. PubMed PMID:30077634. PubMed Central PMC6160342.

  10. 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.
    doi: 10.1038/s41586-018-0135-x. PubMed PMID:29769717. .

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