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

Nightingale, Katie, Lin, Kai-Min, Ravenhill, Benjamin J., Davies, Colin, Nobre, Luis, Fielding, Ceri A. ORCID: https://orcid.org/0000-0002-5817-3153, Ruckova, Eva, Fletcher-Etherington, Alice, Soday, Lior, Nichols, Hester ORCID: https://orcid.org/0000-0002-6814-4364, Sugrue, Daniel, Wang, Eddie C.Y. ORCID: https://orcid.org/0000-0002-2243-4964, Moreno, Pablo, Umrania, Yagnesh, Huttlin, Edward L., Antrobus, Robin, Davison, Andrew J., Wilkinson, Gavin W.G. ORCID: https://orcid.org/0000-0002-5623-0126, Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182, Tomasec, Peter and Weekes, Michael P. 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. 10.1016/j.chom.2018.07.011

Preview

PDF - Published Version Available under License Creative Commons Attribution. Download (3MB) | Preview

Abstract

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:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Additional Information:	This is an open access article under the CCBY license
Publisher:	Elsevier
ISSN:	1931-3128
Funders:	MRC
Date of First Compliant Deposit:	23 August 2018
Date of Acceptance:	25 June 2018
Last Modified:	21 May 2023 19:40
URI:	https://orca.cardiff.ac.uk/id/eprint/114341

Citation Data

Cited 51 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item