Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 6, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2108173119
Keywords
human cytomegalovirus; restriction factor; innate immunity; host-pathogen interaction; Schlafen
Categories
Funding
- Wellcome Trust Senior Clinical Research Fellowship [108070/Z/15/Z]
- Medical Research Council [MR/P001602/1, MR/S00971X/1, MR/V000489/1, MC_UU_12014/3]
- Cambridge Biomedical Research Centre, UK
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In this study, we identified a previously unknown mechanism by which a viral protein degrades the host protein SLFN11, and showed that SLFN11 has inhibitory effects on HCMV infection. This research provides an important resource for studying antiviral immunity and viral immune evasion.
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.
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