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FACT Proteins, SUPT16H and SSRP1, Are Transcriptional Suppressors of HIV-1 and HTLV-1 That Facilitate Viral Latency.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2015 Nov 06; Vol. 290 (45), pp. 27297-27310. Date of Electronic Publication: 2015 Sep 16. - Publication Year :
- 2015
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Abstract
- Our functional genomic RNAi screens have identified the protein components of the FACT (facilitates chromatin transcription) complex, SUPT16H and SSRP1, as top host factors that negatively regulate HIV-1 replication. FACT interacts specifically with histones H2A/H2B to affect assembly and disassembly of nucleosomes, as well as transcription elongation. We further investigated the suppressive role of FACT proteins in HIV-1 transcription. First, depletion of SUPT16H or SSRP1 protein enhances Tat-mediated HIV-1 LTR (long terminal repeat) promoter activity. Second, HIV-1 Tat interacts with SUPT16H but not SSRP1 protein. However, both SUPT16H and SSRP1 are recruited to LTR promoter. Third, the presence of SUPT16H interferes with the association of Cyclin T1 (CCNT1), a subunit of P-TEFb, with the Tat-LTR axis. Removing inhibitory mechanisms to permit HIV-1 transcription is an initial and key regulatory step to reverse post-integrated latent HIV-1 proviruses for purging of reservoir cells. We therefore evaluated the role of FACT proteins in HIV-1 latency and reactivation. Depletion of SUPT16H or SSRP1 protein affects both HIV-1 transcriptional initiation and elongation and spontaneously reverses latent HIV-1 in U1/HIV and J-LAT cells. Similar effects were observed with a primary CD4+ T cell model of HIV-1 latency. FACT proteins also interfere with HTLV-1 Tax-LTR-mediated transcription and viral latency, indicating that they may act as general transcriptional suppressors for retroviruses. We conclude that FACT proteins SUPT16H and SSRP1 play a key role in suppressing HIV-1 transcription and promoting viral latency, which may serve as promising gene targets for developing novel HIV-1 latency-reversing agents.<br /> (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- CD4-Positive T-Lymphocytes physiology
CD4-Positive T-Lymphocytes virology
Cell Cycle Proteins antagonists & inhibitors
Cell Cycle Proteins genetics
Cell Line
Cyclin T physiology
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins genetics
HEK293 Cells
HIV Long Terminal Repeat
HIV-1 genetics
High Mobility Group Proteins antagonists & inhibitors
High Mobility Group Proteins genetics
Host-Pathogen Interactions genetics
Host-Pathogen Interactions physiology
Human T-lymphotropic virus 1 genetics
Humans
Models, Biological
Positive Transcriptional Elongation Factor B physiology
Promoter Regions, Genetic
RNA Interference
Transcription Factors antagonists & inhibitors
Transcription Factors genetics
Transcriptional Elongation Factors antagonists & inhibitors
Transcriptional Elongation Factors genetics
Virus Latency genetics
Cell Cycle Proteins physiology
DNA-Binding Proteins physiology
HIV-1 physiology
High Mobility Group Proteins physiology
Human T-lymphotropic virus 1 physiology
Transcription Factors physiology
Transcriptional Elongation Factors physiology
Virus Latency physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 290
- Issue :
- 45
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26378236
- Full Text :
- https://doi.org/10.1074/jbc.M115.652339