Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 2013 May 31;288(22):15474-80. doi: 10.1074/jbc.M112.416735. Epub 2013 Apr 23.
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.
病毒病原体利用宿主细胞机制为自身谋取利益。在此，我们发现 HIV-1 Vpr（病毒蛋白 R）可负调控端粒酶活性。端粒酶使干细胞和癌细胞能够通过向染色体末端添加端粒序列来逃避细胞衰老。我们发现，Vpr 通过下调端粒酶的催化亚基 TERT 蛋白来抑制端粒酶活性。作为一种分子衔接物，Vpr 增强了 TERT 与 DYRK2 相关 EDD-DDB1-VPRBP E3 连接酶复合物的 VPRBP 底物受体之间的相互作用，导致 TERT 的泛素化增加。相比之下，在 HIV-1 感染的长期非进展者中发现的 Vpr 突变体无法促进 TERT 不稳定。我们的研究结果表明，Vpr 通过劫持宿主 E3 连接酶复合物来抑制端粒酶活性，我们提出了端粒酶失调控的新分子机制，可能与 HIV-1 发病机制有关。
