期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 22, 页码 15474-15480出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.416735
关键词
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资金
- Duncan Family Institute research program grant
- University Cancer Foundation Grant [IRG-08-061-01]
- American Association for Cancer Research-Pancreatic Cancer Action Network [11-20-25-PARK]
- Center for Stem Cell and Developmental Biology transformative pilot grant
- Metastasis Research Center grant
- University of Texas MD Anderson Cancer Center
- National Institutes of Health through The University of Texas MD Anderson Cancer Center [CA016672]
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.
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