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Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins
Hao Chang1,2,3, Lowela Siarot1, Ryosuke Matsuura1,2
1Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Abstract:
Viral protein R (Vpr) is an accessory protein found in various primate lentiviruses, including human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) as well as simian immunodeficiency viruses (SIVs). Vpr modulates many processes during viral lifecycle via interaction with several of cellular targets. Previous studies showed that HIV-1 Vpr strengthened degradation of Mini-chromosome Maintenance Protein10 (MCM10) by manipulating DCAF1-Cul4-E3 ligase in proteasome-dependent pathway. However, whether Vpr from other primate lentiviruses are also associated with MCM10 degradation and the ensuing impact remain unknown. Based on phylogenetic analyses, a panel of primate lentiviruses Vpr/x covering main virus lineages was prepared. Distinct MCM10 degradation profiles were mapped and HIV-1, SIVmus and SIVrcm Vprs induced MCM10 degradation in proteasome-dependent pathway. Colocalization and interaction between MCM10 with these Vprs were also observed. Moreover, MCM10 2-7 interaction region was identified as a determinant region susceptible to degradation. However, MCM10 degradation did not alleviate DNA damage response induced by these Vpr proteins. MCM10 degradation by HIV-1 Vpr proteins was correlated with G2/M arrest, while induction of apoptosis and oligomerization formation of Vpr failed to alter MCM10 proteolysis. The current study demonstrated a distinct interplay pattern between primate lentiviruses Vpr proteins and MCM10.
Insights
Primate lentivirus Vpr proteins, including HIV-1, can degrade Mini-chromosome Maintenance Protein10 (MCM10) via the proteasome pathway. This degradation impacts viral lifecycle but does not alleviate DNA damage responses.
Area of Science:
- Virology
- Molecular Biology
- Cell Biology
Background:
- Viral protein R (Vpr) is an accessory protein in primate lentiviruses like HIV-1 and SIVs.
- Vpr modulates viral lifecycle by interacting with cellular targets.
- Previous studies linked HIV-1 Vpr to MCM10 degradation via the DCAF1-Cul4-E3 ligase complex.
Purpose of the Study:
- To investigate if Vpr proteins from other primate lentiviruses also induce MCM10 degradation.
- To determine the impact of Vpr-mediated MCM10 degradation on cellular processes.
- To identify regions of MCM10 involved in Vpr interaction and degradation.
Main Methods:
- Phylogenetic analysis to select diverse primate lentivirus Vpr proteins.
- Assessing MCM10 degradation profiles in cells expressing different Vpr proteins.
- Co-localization and interaction studies between Vpr and MCM10.
- Identifying MCM10 interaction regions using mutagenesis.
Main Results:
- HIV-1, SIVmus, and SIVrcm Vpr proteins induced MCM10 degradation through the proteasome pathway.
- MCM10 co-localized and interacted with these Vpr proteins.
- The MCM10 2-7 region was identified as crucial for Vpr-mediated degradation.
- MCM10 degradation did not mitigate Vpr-induced DNA damage response.
- HIV-1 Vpr-induced MCM10 degradation correlated with G2/M cell cycle arrest.
Conclusions:
- Primate lentivirus Vpr proteins exhibit distinct patterns of interaction with MCM10.
- Vpr-mediated MCM10 degradation is conserved in certain lentiviruses but does not affect DNA damage response.
- The findings provide insights into lentiviral manipulation of host cell machinery.
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