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Proteasome-dependent disruption of the E3 ubiquitin ligase anaphase-promoting complex by HCMV protein pUL21a. PLoS Pathog 2012;8(7):e1002789

Date

07/14/2012

Pubmed ID

22792066

Pubmed Central ID

PMC3390409

DOI

10.1371/journal.ppat.1002789

Scopus ID

2-s2.0-84864614340 (requires institutional sign-in at Scopus site)   31 Citations

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.

Author List

Fehr AR, Gualberto NC, Savaryn JP, Terhune SS, Yu D

Author

Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anaphase-Promoting Complex-Cyclosome
Apc4 Subunit, Anaphase-Promoting Complex-Cyclosome
Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome
Carrier Proteins
Cell Cycle Proteins
Cell Line, Tumor
Cytomegalovirus
HEK293 Cells
HeLa Cells
Humans
Phosphorylation
Proteasome Endopeptidase Complex
Protein Binding
Sequence Deletion
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases
Ubiquitination
Viral Proteins