Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification, and viral assembly

Li, Hanqi, Fletcher-Etherington, Alice, Hunter, Leah M., Keshri, Swati, Fielding, Ceri A. ORCID: https://orcid.org/0000-0002-5817-3153, Nightingale, Katie, Ravenhill, Benjamin, Nobre, Luis, Potts, Martin, Antrobus, Robin, Crump, Colin M., Rubinsztein, David C., Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182 and Weekes, Michael P. 2024. Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification, and viral assembly. Cell Host & Microbe 32 (4) , pp. 466-478. 10.1016/j.chom.2024.02.013

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Abstract

Human cytomegalovirus (HCMV) is an important human pathogen that regulates host immunity and hijacks host compartments, including lysosomes, to assemble virions. We combined a quantitative proteomic analysis of HCMV infection with a database of proteins involved in vacuolar acidification, revealing Dmx-like protein-1 (DMXL1) as the only protein that acidifies vacuoles yet is degraded by HCMV. Systematic comparison of viral deletion mutants reveals the uncharacterized 7 kDa US33A protein as necessary and sufficient for DMXL1 degradation, which occurs via recruitment of the E3 ubiquitin ligase Kip1 ubiquitination-promoting complex (KPC). US33A-mediated DMXL1 degradation inhibits lysosome acidification and autophagic cargo degradation. Formation of the virion assembly compartment, which requires lysosomes, occurs significantly later with US33A-expressing virus infection, with reduced viral replication. These data thus identify a viral strategy for cellular remodeling, with the potential to employ US33A in therapies for viral infection or rheumatic conditions, in which inhibition of lysosome acidification can attenuate disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	1931-3128
Date of First Compliant Deposit:	22 March 2024
Date of Acceptance:	20 February 2024
Last Modified:	09 May 2024 14:05
URI:	https://orca.cardiff.ac.uk/id/eprint/167500

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