Antiviral Activity of Guanylate-Binding Proteins and Viral Countermeasures
Final Report Abstract
In the present project, we significantly advanced our understanding on the role of GBP proteins as antiviral restriction factors. We found that both GBP2 and GBP5 inhibit many viral pathogens by interfering with furin-mediated processing of their glycoproteins. We also obtained first evidence that GBP2 and GBP5 restrict SARS-CoV-2. In addition, we determined critical domains and structural requirements of their antiviral activity. Finally, we found that GBP2 and GBP5 are expressed under the control of endogenous retroviral RNAs and induced upon HIV-1 infection. Other results provide novel insights into the induction and inhibitory action of innate antiviral mechanisms. They also revealed that some innate antiviral effectors target cellular virus dependency factors rather than the virus directly. Finally, they identified an interesting example of how human cells might exploit endogenized retroviral LTR to produces antiviral factors upon infection with current viral pathogens. Altogether, we feel that the project yielded interesting results but also opened prospects for future studies.
Publications
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(2019). Guanylate-binding proteins 2 and 5 exert broad antiviral activity by inhibiting furin-mediated processing of viral envelope proteins. Cell Reports 27, 2092-2104
Braun, E., Hotter, D., Koepke, L., Zech, F., Groß, R., Müller, J., Wombacher, R., Sutter, K., Dittmer, U., Winkler, M., Simmons, G., Pöhlmann, S., Münch, J., Fackler, O.T., Kirchhoff, F., Sauter, D.
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(2020). HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression. Nucleic Acids Research 48(19), 10890-10908
Srinivasachar Badarinarayan S, Shcherbakova I, Langer S, Koepke L, Preising A, Hotter D, Kirchhoff F, Sparrer KMJ, Schotta G, Sauter D
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(2021). Structural Basis for GTP-induced Dimerization and Antiviral Function of Guanylate-binding Proteins. Proc. Natl. Acad. Sci. USA. 118(15): e2022269118
Cui W, Braun E, Wang W, Tang J, Zheng Y, Slater B, Li N, Chen C, Liu Q, Wang B, Li X, Duan Y, Xiao Y, Ti R, Hotter D, Ji X, Zhang L, Cui J, Xiong Y, Sauter D, Wang Z, Kirchhoff F, Yang H
