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Pingwei Li

Li, Pingwei
Pingwei Li
Professor
Office:
ILSB / Room 2157
Email:
Phone:
979-845-1469
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

  1. Guo, X, Shu, C, Li, H, Pei, Y, Woo, SL, Zheng, J et al.. Cyclic GMP-AMP Ameliorates Diet-induced Metabolic Dysregulation and Regulates Proinflammatory Responses Distinctly from STING Activation. Sci Rep. 2017;7 (1):6355.
    doi: 10.1038/s41598-017-05884-y. PubMed PMID:28743914. PubMed Central PMC5526935.

  2. Zhang, Z, Hu, F, Sung, MW, Shu, C, Castillo-González, C, Koiwa, H et al.. RISC-interacting clearing 3'- 5' exoribonucleases (RICEs) degrade uridylated cleavage fragments to maintain functional RISC in Arabidopsis thaliana. Elife. 2017;6 :.
    doi: 10.7554/eLife.24466. PubMed PMID:28463111. PubMed Central PMC5451212.

  3. Shen, Q, Zeng, D, Zhao, B, Bhatt, VS, Li, P, Cho, JH et al.. The Molecular Mechanisms Underlying the Hijack of Host Proteins by the 1918 Spanish Influenza Virus. ACS Chem. Biol. 2017;12 (5):1199-1203.
    doi: 10.1021/acschembio.7b00168. PubMed PMID:28368102. .

  4. Zhao, B, Yi, G, Du, F, Chuang, YC, Vaughan, RC, Sankaran, B et al.. Structure and function of the Zika virus full-length NS5 protein. Nat Commun. 2017;8 :14762.
    doi: 10.1038/ncomms14762. PubMed PMID:28345656. PubMed Central PMC5378950.

  5. Zhao, B, Shu, C, Gao, X, Sankaran, B, Du, F, Shelton, CL et al.. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins. Proc. Natl. Acad. Sci. U.S.A. 2016;113 (24):E3403-12.
    doi: 10.1073/pnas.1603269113. PubMed PMID:27302953. PubMed Central PMC4914169.

  6. Li, T, Cheng, H, Yuan, H, Xu, Q, Shu, C, Zhang, Y et al.. Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response. Sci Rep. 2016;6 :19049.
    doi: 10.1038/srep19049. PubMed PMID:26754564. PubMed Central PMC4709567.

  7. Yi, G, Wen, Y, Shu, C, Han, Q, Konan, KV, Li, P et al.. Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses. J. Virol. 2015;90 (1):254-65.
    doi: 10.1128/JVI.01720-15. PubMed PMID:26468527. PubMed Central PMC4702547.

  8. Weaver, J, Watts, T, Li, P, Rye, HS. Structural basis of substrate selectivity of E. coli prolidase. PLoS ONE. 2014;9 (10):e111531.
    doi: 10.1371/journal.pone.0111531. PubMed PMID:25354344. PubMed Central PMC4213023.

  9. Shu, C, Li, X, Li, P. The mechanism of double-stranded DNA sensing through the cGAS-STING pathway. Cytokine Growth Factor Rev. 2014;25 (6):641-8.
    doi: 10.1016/j.cytogfr.2014.06.006. PubMed PMID:25007740. PubMed Central PMC4254336.

  10. Li, X, Shu, C, Yi, G, Chaton, CT, Shelton, CL, Diao, J et al.. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity. 2013;39 (6):1019-31.
    doi: 10.1016/j.immuni.2013.10.019. PubMed PMID:24332030. PubMed Central PMC3886715.

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