HIV-1 Vpr Protein Enhances Proteasomal Degradation of MCM10 DNA Replication Factor through the Cul4-DDB1[VprBP] E3 Ubiquitin Ligase to Induce G2/M Cell Cycle Arrest

Bizhan Romani,Nima Shaykh Baygloo,Mohammad Reza Aghasadeghi,Elham Allahbakhshi

doi:10.1074/jbc.m115.641522

Abstract

Human immunodeficiency virus type 1 Vpr is an accessory protein that induces G2/M cell cycle arrest. It is well documented that interaction of Vpr with the Cul4-DDB1[VprBP] E3 ubiquitin ligase is essential for the induction of G2/M arrest. In this study, we show that HIV-1 Vpr indirectly binds MCM10, a eukaryotic DNA replication factor, in a Vpr-binding protein (VprBP) (VprBP)-dependent manner. Binding of Vpr to MCM10 enhanced ubiquitination and proteasomal degradation of MCM10. G2/M-defective mutants of Vpr were not able to deplete MCM10, and we show that Vpr-induced depletion of MCM10 is related to the ability of Vpr to induce G2/M arrest. Our study demonstrates that MCM10 is the natural substrate of the Cul4-DDB1[VprBP] E3 ubiquitin ligase whose degradation is regulated by VprBP, but Vpr enhances the proteasomal degradation of MCM10 by interacting with VprBP.

Highlights

maintenance complex component 10 (MCM10) regulates initiation of eukaryotic genome replication
Our study demonstrates that MCM10 is the natural substrate of the Cul4-DDB1[Vpr-binding protein (VprBP)] E3 ubiquitin ligase whose degradation is regulated by VprBP, but Vpr enhances the proteasomal degradation of MCM10 by interacting with VprBP
We demonstrated that HIV-1 Vpr enhances proteasomal degradation of MCM10

Summary

Background

MCM10 regulates initiation of eukaryotic genome replication. Results: HIV-1 Vpr enhances proteasomal degradation of MCM10. Conclusion: HIV-1 Vpr-mediated degradation of MCM10 is essential for induction of G2/M cell cycle arrest. Significance: Our study reveals a novel protein target for HIV-1 Vpr whose degradation is involved in the induction of G2/M cell cycle arrest by the virus. It is well documented that interaction of Vpr with the Cul4-DDB1[VprBP] E3 ubiquitin ligase is essential for the induction of G2/M arrest. Our study demonstrates that MCM10 is the natural substrate of the Cul4-DDB1[VprBP] E3 ubiquitin ligase whose degradation is regulated by VprBP, but Vpr enhances the proteasomal degradation of MCM10 by interacting with VprBP. Retroviral protein Vpx, which is encoded by HIV-2 and a number of closely related simian immunodeficiency viruses, redirects the E3 ubiquitin ligase for proteasomal degradation of SAMHD1 [7,8,9].

The abbreviations used are

Experimental Procedures

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Discussion