High-definition analysis of host protein stability during human cytomegalovirus infection reveals antiviral factors and viral evasion mechanisms

Nightingale, K. et al. (2018) High-definition analysis of host protein stability during human cytomegalovirus infection reveals antiviral factors and viral evasion mechanisms. Cell Host and Microbe, 24(3), 447-460.e11. (doi: 10.1016/j.chom.2018.07.011) (PMID:30122656) (PMCID:PMC6146656)

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Human cytomegalovirus (HCMV) is an important pathogen with multiple immune evasion strategies, including virally facilitated degradation of host antiviral restriction factors. Here, we describe a multiplexed approach to discover proteins with innate immune function on the basis of active degradation by the proteasome or lysosome during early-phase HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, with high confidence we identified 35 proteins enriched in antiviral restriction factors. A final screen employed a comprehensive panel of viral mutants to predict viral genes that target >250 human proteins. This approach revealed that helicase-like transcription factor (HLTF), a DNA helicase important in DNA repair, potently inhibits early viral gene expression but is rapidly degraded during infection. The functionally unknown HCMV protein UL145 facilitates HLTF degradation by recruiting the Cullin4 E3 ligase complex. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.

Item Type:Articles
Additional Information:This work was supported by a Wellcome Trust Senior Clinical Research Fellowship (108070/Z/15/Z) to M.P.W., a strategic award to Cambridge Institute for Medical Research from the Wellcome Trust (100140), MRC project grants to G.W.G.W., P.T., E.C.Y.W., and R.J.S. (MR/L018373/1, MR/P001602/1), a Wellcome Trust Program grant (WT090323MA) to G.W.G.W., E.C.Y.W., and P.T., and an MRC Program grant (MC_UU_12014/3) to A.J.D. This study was additionally supported by the Cambridge Biomedical Research Center, UK.
Glasgow Author(s) Enlighten ID:Davison, Professor Andrew
Authors: Nightingale, K., Lin, K.-M., Ravenhill, B. J., Davies, C., Nobre, L., Fielding, C. A., Ruckova, E., Fletcher-Etherington, A., Soday, L., Nichols, H., Sugrue, D., Wang, E. C.Y., Moreno, P., Umrania, Y., Huttlin, E. L., Antrobus, R., Davison, A. J., Wilkinson, G. W.G., Stanton, R. J., Tomasec, P., and Weekes, M. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Cell Host and Microbe
Publisher:Elsevier (Cell Press)
ISSN (Online):1934-6069
Published Online:16 August 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Host and Microbe 24(3): 447-460.e11
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH