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Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

Nightingale, Katie, Potts, Martin, Hunter, Leah M., Fielding, Ceri A. ORCID:, Zerbe, Cassie M., Fletcher-Etherington, Alice, Nobre, Luis, Wang, Eddie C. Y. ORCID:, Strang, Blair L., Houghton, Jack W., Antrobus, Robin, Suarez, Nicolas M., Nichols, Jenna, Davison, Andrew J., Stanton, Richard J. ORCID: and Weekes, Michael P. 2022. Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. Proceedings of the National Academy of Sciences 119 (6) , e2108173119. 10.1073/pnas.2108173119

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Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate, and adaptive immunity. We have employed two orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins down-regulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterized, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Additional Information: This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Publisher: National Academy of Sciences
ISSN: 0027-8424
Funders: MRC
Date of First Compliant Deposit: 14 February 2022
Date of Acceptance: 14 December 2021
Last Modified: 29 Nov 2022 10:48

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