Human Cytomegalovirus Inactivates the G0/G1-APC/C Ubiquitin Ligase by Cdh1 Dissociation

Wiebusch, Lüder; Bach, Miriam; Uecker, Rail; Hagemeier, Christian

doi:10.4161/cc.4.10.2077

Cited by 44 publications

(52 citation statements)

References 38 publications

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“…We and others have found that, upon HCMV infection, the APC4 and APC5 subunits are degraded, the TPR subunits dissociate from the catalytic core and Cdh1, Cdh1 is hyperphosphorylated, and APC/C substrates accumulate (5,8,9). We also demonstrated that the viral kinase UL97 is capable of phosphorylating the APC/C coactivator Cdh1 on several sites, but in the context of infection, UL97 is not required for APC/C inactivation and disassembly (10).…”

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confidence: 73%

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Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, APC4, and APC5

Clark

Spector

2015

J Virol

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Human cytomegalovirus (HCMV) deregulates the cell cycle by several means, including inactivation of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. Viral proteins UL97 and UL21a, respectively, affect the APC/C by phosphorylation of APC/C coactivator Cdh1 and by inducing the degradation of subunits APC4 and APC5, which along with APC1 form the APC/C platform subcomplex. The aim of this study was to further characterize the mechanism of APC/C inactivation and define the relative contributions of UL21a and UL97 to APC/C substrate accumulation and to viral growth. We show that in uninfected cells, UL21a but not UL97 can disrupt APC/C function, leading to the accumulation of substrates. We find that UL21a is necessary and sufficient to induce the degradation of APC1, in addition to the previously reported APC4 and APC5. We also demonstrate that there is a previously unreported cellular mechanism for a specific decrease in the levels of all three platform subunits, APC1, APC4, and APC5, upon the depletion of any one of these subunits or of subunit APC8. Finally, we show that at a low multiplicity of infection, either UL97 or UL21a can partially complement a growth-defective mutant virus lacking both UL21a and UL97, with significantly greater benefit afforded by the expression of both proteins. This double mutant also can be partially rescued by inactivation of the APC/C using small interfering RNAs against specific subunits. These results further our understanding of HCMV's interaction with the cell cycle machinery and reveal a new cellular pattern of APC/C subunit downmodulation. IMPORTANCEHCMV lytic infection subverts the host cell cycle machinery in multiple ways. A major effect is inactivation of the APC/C, which plays a central role in the control of cell cycle progression. This study provides further insight into the mechanism of inactivation. We discovered that the APC1 subunit, which along with APC4 and APC5 form the platform subcomplex of the APC/C, is an additional target of the degradation induced by HCMV protein UL21a. This study also shows for the first time that there is a unique cellular process in uninfected cells whereby depletion of APC1, APC4, APC5, or APC8 recapitulates the pattern of HCMV-mediated APC/C subunit degradation. H uman cytomegalovirus (HCMV) infects the majority of the human population, causing significant morbidity and mortality in immunocompromised individuals, such as transplant patients and those with HIV. HCMV is also the leading viral cause of birth defects. These manifest as neural developmental defects ranging from hearing loss to calcification of the developing brain and death at a rate of 1 or 2 per 1,000 newborns.HCMV lytic infection both modulates and is influenced by the host cell cycle. The virus preferentially infects cells in G 0 or G 1 . Infection in other phases of the cell cycle results in a delay of immediate early gene expression until completion of mitosis in the case of a G 2 infection. Infection during S phase remains unproductive i...

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confidence: 73%

“…Early in infection, the virus causes a stimulation of resting cells into the cell cycle and subsequent arrest at the G 1 /S border (1)(2)(3). The infection inhibits host DNA replication, affects cyclin levels (4), prevents host DNA replication licensing (5)(6)(7), and inhibits the anaphase-promoting complex/cyclosome (APC/C) (8)(9)(10).…”

mentioning

confidence: 99%

Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, APC4, and APC5

Clark

Spector

2015

J Virol

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“…22), like the CAV protein Apoptin 23 and HCMV. 24 These results led us to hypothesize that E2 could induce abnormal mitoses through such a mechanism. As APC cellular inhibitors act by direct binding to Cdh1 or Cdc20, we investigated whether E2 from high-risk HPVs could interact with these two proteins.…”

Section: High-risk Hpv E2 Proteins Block Cells In G 2 /Mmentioning

confidence: 99%

High-Risk But Not Low-Risk HPV E2 Proteins Bind to the APC Activators Cdh1 and Cdc20 and Cause Genomic Instability

Bellanger¹,

Blachon²,

Méchali³

et al. 2005

Cell Cycle

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“…Having shown that MCMV, unlike HCMV, fails to be negatively regulated by cyclin A2-CDK, we asked whether this difference may also be reflected at the level of virus-mediated regulation of cyclin A2-CDK activity during the course of lytic infection. To address this point, we used an approach that has been successfully employed in a number of studies to investigate the influence of HCMV on cyclin-dependent kinases and other cell cycle-related activities (5,28,71,72,75). The main principle of this approach is to infect cells (mostly nontransformed fibroblasts) that have been synchronized in G 0 /G 1 by growth factor deprivation or contact inhibition.…”

Section: Cyclin A2 Interferes With Hcmv Gene Expression In a Cdk-depementioning

confidence: 99%

Inhibition of Human Cytomegalovirus Immediate-Early Gene Expression by Cyclin A2-Dependent Kinase Activity

Oduro

Uecker

Hagemeier

et al. 2012

J Virol

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Human cytomegalovirus (HCMV) starts its lytic replication cycle only in the G 0 /G 1 phase of the cell division cycle. S/G 2 cells can be infected but block the onset of immediate-early (IE) gene expression. This block can be overcome by inhibition of cyclin-dependent kinases (CDKs), suggesting that cyclin A2, the only cyclin with an S/G 2 -specific activity profile, may act as a negative regulator of viral gene expression. To directly test this hypothesis, we generated derivatives of an HCMV-permissive glioblastoma cell line that express cyclin A2 in a constitutive, cell cycle-independent manner. We demonstrate that even moderate cyclin A2 overexpression in G 1 was sufficient to severely compromise the HCMV replicative cycle after high-multiplicity infection. This negative effect was composed of a strong but transient inhibition of IE gene transcription and a more sustained alteration of IE mRNA processing, resulting in reduced levels of UL37 and IE2, an essential transactivator of viral early gene expression. Consistently, cyclin A2-overexpressing cells showed a strong delay of viral early and late gene expression, as well as virus reproduction. All effects were dependent on CDK activity, as a cyclin A2 mutant deficient in CDK binding was unable to interfere with the HCMV infectious cycle. Interestingly, murine CMV, whose IE gene expression is known to be cell cycle independent, is not affected by cyclin A2. Instead, it upregulates cyclin A2-associated kinase activity upon infection. Understanding the mechanisms behind the HCMV-specific action of cyclin A2-CDK might reveal new targets for antiviral strategies.

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Human Cytomegalovirus Inactivates the G0/G1-APC/C Ubiquitin Ligase by Cdh1 Dissociation

Cited by 44 publications

References 38 publications

Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, APC4, and APC5

Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, APC4, and APC5

High-Risk But Not Low-Risk HPV E2 Proteins Bind to the APC Activators Cdh1 and Cdc20 and Cause Genomic Instability

Inhibition of Human Cytomegalovirus Immediate-Early Gene Expression by Cyclin A2-Dependent Kinase Activity

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