title: HIV-1 Vpr protein inhibits telomerase activity via the EDD-DDB1-VPRBP E3 ligase complex.
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.
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shailbala
authors.initials: S
authors.lastname: Singh
authors.forename: Hae-Yun
authors.initials: HY
authors.lastname: Jung
authors.forename: Guojun
authors.initials: G
authors.lastname: Yang
authors.forename: Sohee
authors.initials: S
authors.lastname: Jun
authors.forename: K Jagannadha
authors.initials: KJ
authors.lastname: Sastry
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Park
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D019098:Telomerase; D044767:Ubiquitin-Protein Ligases; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000097603:Dyrk Kinases; C091435:DDB1 protein, human; C514912:vpr protein, Human immunodeficiency virus 1; C117617:UBR5 protein, human; C530533:DCAF1 protein, human; C509186:TERT protein, human
keywords: DYRK2; EDD; HIV-1; Protein Degradation; TERT; Telomerase; Telomeres; Ubiquitination; VPRBP; Vpr