Research Interests
We work on innate immunity and mitochondrial quality control, focusing on DNA induced innate immune signaling pathway, the PINK1-Parkin pathway, autoimmune diseases, bacteria and inflammation. The laboratory uses cell biology, structural biology, biochemistry and immunology methods to study the core mechanisms and potential applications of innate immunity and mitochondrial regulation. Our current research is mainly focused on: 1) mitochondrial dynamics and quality control, and innate immunity regulation mechanism; 2) bacterial cyclic nucleotide metabolism pathway and immune regulation mechanism; 3) potential applications in the treatment of autoimmune diseases and neurodegenerative diseases.
Scientific Contributions
The PINK1-Parkin pathway could induce mitophagy when mitochondrial damage happened. PINK1 is the upstream kinase of E3 ligase Parkin. The PINK1-Parkin pathway is closely related to Parkinson's disease. We identified the activation mechanism of PINK1-Parkin signaling pathway and found a positive feedback mechanism of Parkin during the activation (Figure 1).
Figure1. The activation mechanism of Parkin triggered by PINK1
In the field of DNA innate immunity, our work mainly focuses on the activation mechanism of the downstream adapter protein STING in the cGAS-STING pathway. We determined the structure of full-length STING in its inactive and active states, paving the way for further mechanistic studies as well as the development of agonists and antagonists of STING for treating human diseases (Figure 2). We also determined the structure of STING-TBK1 complex, revealing for the first time the structure of the STING C-terminal tail that binds to TBK1 (Figure 2). Our work elucidates the mechanism of STING activation by the second messenger cGAMP. Our research also elucidates the mechanism of the TBK1-STING-IRF3 phosphorylation signalling (Figure 2).
Figure 2. The structures of STING and STING-TBK1 complex
Selected Publications
1.
Zhang C⃰, Shang G ⃰, Gui X, Bai X, Zhang X, Chen J. Z. (2019). Structural Basis of STING Binding with and Phosphorylation by TBK1.
Nature. 567: 394-398.
2.
Zhang C, Wang R, Liu Z, Bunker E, Lee S, Giuntini M, Chapnick D, and Liu X. (2019). The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1’s association with the mitochondrial protein TOM20.
J Biol Chem. 294: 7472-7487.
3. Shang G ⃰,
Zhang C ⃰, Chen J. Z, Bai X, Zhang X. (2019). Cryo-EM Structures of STING Reveal Its Mechanism of Activation by Cyclic GMP-AMP.
Nature. 567: 389-393.
4.
Zhang C ⃰, Liu Z ⃰, Bunker E ⃰, Ramirez A, Lee S, Peng Y, Tan AC, Eckhardt SG, Chapnick DA, Liu X. (2017). Sorafenib Targets the Mitochondrial Electron Transport Chain Complexes and ATP Synthase to Activate the PINK1-Parkin Pathway and Modulate Cellular Drug Response.
J Biol Chem. 292: 15105-15120.
5.
Zhang, C., Lee, S., Peng, Y., Bunker, E., Shen, C., Giaime, E., Shen, J., Shen, J., Zhou, Z., and Liu, X. (2015). A chemical genetic approach to probe the function of PINK1 in regulating mitochondrial dynamics.
Cell research. 25(3):394-7.
6.
Zhang, C., S. Lee, Y. Peng, E. Bunker, E. Giaime, J. Shen, Z. Zhou, and X. Liu. (2014). PINK1 Triggers Autocatalytic Activation of Parkin to Specify Cell Fate Decisions.
Curr Biol. 24:1854-65.
7. Lee, S ⃰.,
Zhang, C ⃰., and Liu, X. (2014). Role of Glucose Metabolism and ATP in Maintaining PINK1 Levels During Parkin-mediated Mitochondrial Damage Responses.
J Biol Chem. 290(2):904-17.
8. Liu, S.,
C. Zhang, T. Su, T. Wei, D. Zhu, K. Wang, Y. Huang, Y. Dong, K. Yin, S. Xu, P. Xu, and L. Gu. (2014). Crystal structure of DszC from
Rhodococcus sp. XP at 1.79 A.
Proteins. 82:1708-20.
9. Liu, S ⃰.,
Zhang, C ⃰., Li, N., Niu, B., Liu, M., Liu, X., Wei, T., Zhu, D., Huang, Y., Xu, S., and Gu, L. (2012). Structural insight into the ISC domain of VibB from Vibrio cholerae at atomic resolution: a snapshot just before the enzymatic reaction.
Acta Crystallogr D Biol Crystallogr. 68:1329-38.
10. Li, N.,
Zhang, C., Li, B., Liu, X., Huang, Y., Xu, S., and Gu, L. (2012). Unique iron coordination in iron-chelating molecule vibriobactin helps Vibrio cholerae evade mammalian siderocalin-mediated immune response.
J Biol Chem. 287:8912-8919.
