PhD project

Supervisor: Geoffrey L Smith and Sumana Sanyal

Human cells possess many proteins that are able to restrict the replication of infecting viruses, and these are called virus restriction factors. These proteins may recognise a virus pathogen-associated molecular pattern (PAMP) and thereafter activate innate immunity, or bind to some virus protein or nucleic acid to diminish virus replication or spread. This project aims to identify and study the mechanisms of action of a group of virus restriction factors that are E3 ubiquitin ligases, focusing initially on TRIM25, and study their action against viruses that have genomes of either DNA (poxviruses and herpes viruses) or RNA (flaviviruses).

A proteomic study of human fibroblasts infected with vaccinia virus indicated that 265 cellular proteins were down-regulated (Soday et al., 2019) and it was hypothesized that these proteins were restriction factors for poxviruses and that is why the virus had evolved a way to remove them. This hypothesis was proved correct for histone deacetylase (HDAC)4 (Lu et al., 2019), HDAC5 (Soday et al., 2019) and the E3 ligase TRIM5α (Zhao et al., 2023). Several other E3 ligases are down-regulated during vaccinia virus infection and these include TRIM25 (Soday et al., 2019). Preliminary data show that TRIM25 has antiviral activity against both poxviruses and flaviviruses (Zhang et al 2018), which can either be via its ubiquitin ligase or its additional ISG15 ligase activity (Munnur et al, 2021). Therefore, its mechanism of action will be investigated. The project will also investigate the mechanism by which the degradation of TRIM25 is induced following infection by poxviruses and whether this is a universal feature of immune evasion by DNA and RNA viruses.

The student appointed will be supervised jointly by Geoffrey Smith and Sumana Sanyal with daily supervision provided by postdoctoral members of their research teams.

Publications:

• Soday, L., Lu, Y., Albarnaz, J.D., Davies, C., Antrobus, R., Smith, G.L., & Weekes, M.P. (2019). Quantitative temporal viromics of vaccinia virus infection reveals regulation of histone deacetylases by a virus interferon antagonist. Cell Reports 27, 1920-33 e7.
• Lu, Y., Stuart, J.H., Talbot-Cooper, C., Agrawal-Singh, SA., Huntly, B., Smid, A.I., Snowden, J.S., Dupont, L., & Smith, G.L. (2019) Histone deacetylase 4 promotes type I interferon signalling, restricts DNA viruses, and is degraded by vaccinia virus protein C6. Natl. Acad. Sci. USA 116, 11997-12006.
• Zhao, Y., Lu, Y., Richardson, S., Sreekumar, M., Albarnaz, J.D. & Smith, G.L. (2023). TRIM5α restricts poxviruses and is antagonized by CypA and viral protein C6. Nature, August 9: Doi 1038/s41586-023-06401-0
• Munnur D et al and Sanyal S. Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection. (2021) Nature Immunology 22(11): 1416-1427
• Jahan AS et al and Sanyal S. OTUB1 activates RIG-I dependent immune signaling and is targeted for proteasomal degradation by NS1 (2020) Cell Reports 30(5): 1570-1584.e6
• Zhang J et al and Sanyal S. Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production (2018) Cell Host Microbe. 23 (6): 819-831