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

Cell Host Microbe. 2024 Mar 5:S1931-3128(24)00055-6. doi: 10.1016/j.chom.2024.02.013. Online ahead of print.ABSTRACTHuman 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.PMID:38479395 | DOI:10.1016/j.chom.2024.02.013
Source: Cell Host and Microbe - Category: Microbiology Authors: Source Type: research