Kim, E. T., Dybas, J. M., Kulej, K., Reyes, E. D., Price, A. M., Akhtar, L. N., Orr, A., Garcia, B. A., Boutell, C. and Weitzman, M. D. (2021) Comparative proteomics identifies Schlafen 5 (SLFN5) as a herpes simplex virus restriction factor that suppresses viral transcription. Nature Microbiology, 6, pp. 234-245. (doi: 10.1038/s41564-020-00826-3) (PMID:33432153) (PMCID:PMC7856100)
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Abstract
Intrinsic antiviral host factors confer cellular defence by limiting virus replication and are often counteracted by viral countermeasures. We reasoned that host factors that inhibit viral gene expression could be identified by determining proteins bound to viral DNA (vDNA) in the absence of key viral antagonists. Herpes simplex virus 1 (HSV-1) expresses E3 ubiquitin-protein ligase ICP0 (ICP0), which functions as an E3 ubiquitin ligase required to promote infection. Cellular substrates of ICP0 have been discovered as host barriers to infection but the mechanisms for inhibition of viral gene expression are not fully understood. To identify restriction factors antagonized by ICP0, we compared proteomes associated with vDNA during HSV-1 infection with wild-type virus and a mutant lacking functional ICP0 (ΔICP0). We identified the cellular protein Schlafen family member 5 (SLFN5) as an ICP0 target that binds vDNA during HSV-1 ΔICP0 infection. We demonstrated that ICP0 mediates ubiquitination of SLFN5, which leads to its proteasomal degradation. In the absence of ICP0, SLFN5 binds vDNA to repress HSV-1 transcription by limiting accessibility of RNA polymerase II to viral promoters. These results highlight how comparative proteomics of proteins associated with viral genomes can identify host restriction factors and reveal that viral countermeasures can overcome SLFN antiviral activity.
| Item Type: | Articles |
|---|---|
| Additional Information: | C.B. was supported by a Medical Research Council grant no. MC_UU_12014/5. Work in the Weitzman laboratory was supported in part by grants from the National Institutes of Health (grant nos. AI115104 and NS082240 to M.D.W.) and funds from the Children’s Hospital of Philadelphia. A.M.P. was supported by the National Cancer Institute T32 Training Grant in Tumor Virology no. T32-CA115299 and Individual National Research Service Award no. F32-AI138432. J.M.D. was supported by the Individual National Research Service Award no. F32-AI147587. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Orr, Mrs Anne and Boutell, Dr Chris |
| Authors: | Kim, E. T., Dybas, J. M., Kulej, K., Reyes, E. D., Price, A. M., Akhtar, L. N., Orr, A., Garcia, B. A., Boutell, C., and Weitzman, M. D. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | Nature Microbiology |
| Publisher: | Nature Research |
| ISSN: | 2058-5276 |
| ISSN (Online): | 2058-5276 |
| Published Online: | 11 January 2021 |
| Copyright Holders: | Copyright © 2021 The Authors, under exclusive licence to Springer Nature Limited |
| First Published: | First published in Nature Microbiology 6:234–245 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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