Abstract
Viral pathogens utilize host cell machinery for their benefits. Herein, we identify that HIV-1 Vpr (viral protein R) negatively modulates telomerase activity. Telomerase enables stem and cancer cells to evade cell senescence by adding telomeric sequences to the ends of chromosomes. We found that Vpr inhibited telomerase activity by down-regulating TERT protein, a catalytic subunit of telomerase. As a molecular adaptor, Vpr enhanced the interaction between TERT and the VPRBP substrate receptor of the DYRK2-associated EDD-DDB1-VPRBP E3 ligase complex, resulting in increased ubiquitination of TERT. In contrast, the Vpr mutant identified in HIV-1-infected long-term nonprogressors failed to promote TERT destabilization. Our results suggest that Vpr inhibits telomerase activity by hijacking the host E3 ligase complex, and we propose the novel molecular mechanism of telomerase deregulation in possibly HIV-1 pathogenesis.
Keywords:
DYRK2; EDD; HIV-1; Protein Degradation; TERT; Telomerase; Telomeres; Ubiquitination; VPRBP; Vpr.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dyrk Kinases
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HIV Infections / genetics
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HIV Infections / metabolism*
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HIV Infections / pathology
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HIV-1 / genetics
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HIV-1 / metabolism*
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HeLa Cells
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Humans
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Jurkat Cells
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Stability
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proteolysis*
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Telomerase / genetics
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Telomerase / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination*
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vpr Gene Products, Human Immunodeficiency Virus / genetics
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vpr Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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Carrier Proteins
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DDB1 protein, human
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DNA-Binding Proteins
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vpr Gene Products, Human Immunodeficiency Virus
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vpr protein, Human immunodeficiency virus 1
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UBR5 protein, human
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Ubiquitin-Protein Ligases
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Protein-Tyrosine Kinases
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DCAF1 protein, human
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Protein Serine-Threonine Kinases
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TERT protein, human
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Telomerase