ArticlePLoS pathogens2012
Proteasome-dependent disruption of the E3 ubiquitin ligase anaphase-promoting complex by HCMV protein pUL21a.
Article in PLoS pathogens, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Viral inhibition of the anaphase promoting complex enhances replication by elevating nucleotide pools.PLoS pathogens · 2026Article
- A murine cytomegalovirus cell cycle regulator (m54.5p) evolved within the conserved viral DNA polymerase gene.PLoS pathogens · 2026Article
- The effective multiplicity of infection for HCMV depends on the activity of the cellular 20S proteasome.Journal of virology · 2025Article
- Review
- Virus-host protein interactions as footprints of human cytomegalovirus replication.Current opinion in virology · 2022Review
- Virus-induced FoxO factor facilitates replication of human cytomegalovirus.Archives of virology · 2022Article
- Viruses utilize ubiquitination systems to escape TLR/RLR-mediated innate immunity.Frontiers in immunology · 2022Review
- Emerging Mechanisms of GmBio · 2021Review
- Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication Is Independent of Anaphase-Promoting Complex Activity.Journal of virology · 2020Article
- Network mechanisms and dysfunction within an integrated computational model of progression through mitosis in the human cell cycle.PLoS computational biology · 2020Article
- Human Cytomegalovirus Primary Infection and Reactivation: Insights From Virion-Carried Molecules.Frontiers in microbiology · 2020Review
- Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus.PLoS pathogens · 2017Article
- An intein-mediated modulation of protein stability system and its application to study human cytomegalovirus essential gene function.Scientific reports · 2016Article
- Article
- Human cytomegalovirus riding the cell cycle.Medical microbiology and immunology · 2015Review
- The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics.Expert review of proteomics · 2014Article
- The 19S proteasome activator promotes human cytomegalovirus immediate early gene expression through proteolytic and nonproteolytic mechanisms.Journal of virology · 2014Article
- PUL21a-Cyclin A2 interaction is required to protect human cytomegalovirus-infected cells from the deleterious consequences of mitotic entry.PLoS pathogens · 2014Article
- An epistatic relationship between the viral protein kinase UL97 and the UL133-UL138 latency locus during the human cytomegalovirus lytic cycle.Journal of virology · 2014Article
- Article
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Authors and funding
5 authors.
Funding
Abstract
The anaphase-promoting complex (APC) is an E3 ubiquitin ligase which controls ubiquitination and degradation of multiple cell cycle regulatory proteins. During infection, human cytomegalovirus (HCMV), a widespread pathogen, not only phosphorylates the APC coactivator Cdh1 via the multifunctional viral kinase pUL97, it also promotes degradation of APC subunits via an unknown mechanism. Using a proteomics approach, we found that a recently identified HCMV protein, pUL21a, interacted with the APC. Importantly, we determined that expression of pUL21a was necessary and sufficient for proteasome-dependent degradation of APC subunits APC4 and APC5. This resulted in APC disruption and required pUL21a binding to the APC. We have identified the proline-arginine amino acid pair at residues 109-110 in pUL21a to be critical for its ability to bind and regulate the APC. A point mutant virus in which proline-arginine were mutated to alanines (PR-AA) grew at wild-type levels. However, a double mutant virus in which the viral ability to regulate the APC was abrogated by both PR-AA point mutation and UL97 deletion was markedly more attenuated compared to the UL97 deletion virus alone. This suggests that these mutations are synthetically lethal, and that HCMV exploits two viral factors to ensure successful disruption of the APC to overcome its restriction on virus infection. This study reveals the HCMV protein pUL21a as a novel APC regulator and uncovers a unique viral mechanism to subvert APC activity.
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