| Autor: |
Yurkovetskiy L; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., Guney MH; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., Kim K; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., Goh SL; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., McCauley S; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., Dauphin A; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., Diehl WE; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA., Luban J; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA. jeremy.luban@umassmed.edu.; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. jeremy.luban@umassmed.edu. |
| Abstrakt: |
Host factors that silence provirus transcription in CD4 + memory T cells help HIV-1 escape eradication by the host immune system and by antiviral drugs 1 . These same factors, however, must be overcome for HIV-1 to propagate. Here we show that Vpx and Vpr encoded by diverse primate immunodeficiency viruses activate provirus transcription. Vpx and Vpr are adaptor proteins for the DCAF1-CUL4A/B E3 ubiquitin ligase that degrade SAMHD1 and increase reverse transcription 2-4 . Nonetheless, Vpx and Vpr have effects on reporter gene expression that are not explained by SAMHD1 degradation 5-8 . A screen for factors that mimic these effects identified the human silencing hub (HUSH) complex, FAM208A (TASOR/RAP140), MPHOSPH8 (MPP8), PPHLN1 (PERIPHILIN) and MORC2 9-13 . Vpx associated with the HUSH complex and decreased steady-state level of these proteins in a DCAF1/CUL4A/B/proteasome-dependent manner 14,15 . Replication kinetics of HIV-1 and SIV MAC was accelerated to a similar extent by vpx or FAM208A knockdown. Finally, vpx increased steady-state levels of LINE-1 ORF1p, as previously described for FAM208A disruption 11 . These results demonstrate that the HUSH complex represses primate immunodeficiency virus transcription, and that, to counteract this restriction, viral Vpx or Vpr proteins degrade the HUSH complex. |
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