Details

Autor(en) / Beteiligte

• Li, Hanqi
• Fletcher-Etherington, Alice
• Hunter, Leah M.
• Keshri, Swati
• Fielding, Ceri A.
• Nightingale, Katie
• Ravenhill, Benjamin
• Nobre, Luis
• Potts, Martin
• Antrobus, Robin
• Crump, Colin M.
• Rubinsztein, David C.
• Stanton, Richard J.
• Weekes, Michael P.

Titel

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

Ist Teil von

• Cell host & microbe, 2024-04, Vol.32 (4), p.466-478.e11

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Systematic proteomic definition of the function of seven HCMV proteins•HCMV US33A hijacks the KPC E3 ligase and is necessary and sufficient to degrade DMXL1•DMXL1 degradation inhibits lysosomal acidification and autophagic cargo degradation•DMXL1 degradation inhibits virion assembly compartment formation and viral release Li et al. report that human cytomegalovirus (HCMV) US33A degrades DMXL1, a key regulator of vacuolar acidification, to remodel host lysosomes and autophagy. The US33A protein hijacks the cellular KPC E3 ligase complex, inhibiting HCMV assembly and release, as well as suppressing herpes simplex virus replication.