Fused in sarcoma silences HIV gene transcription and maintains viral latency through suppressing AFF4 gene activation
Victor, Rachel A
Schwartz, Jacob C
AffiliationUniv Arizona, Dept Chem & Biochem
KeywordsAF4/FMR2 family member 4
Cyclin kinase 9
Elongation factor for RNA polymerase II 2—ELL2
Fused in sarcoma—FUS
Human immunodeficiency virus
Positive transcription elongation factor b
RNA polymerase II
Super elongation complex
MetadataShow full item record
CitationKrasnopolsky, S., Marom, L., Victor, R. A., Kuzmina, A., Schwartz, J. C., Fujinaga, K., & Taube, R. (2019). Fused in sarcoma silences HIV gene transcription and maintains viral latency through suppressing AFF4 gene activation. Retrovirology, 16(1), 16.
Rights© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractBackground: The human immunodeficiency virus (HIV) cell reservoir is currently a main obstacle towards complete eradication of the virus. This infected pool is refractory to anti-viral therapy and harbors integrated proviruses that are transcriptionally repressed but replication competent. As transcription silencing is key for establishing the HIV reservoir, significant efforts have been made to understand the mechanism that regulate HIV gene transcription, and the role of the elongation machinery in promoting this step. However, while the role of the super elongation complex (SEC) in enhancing transcription activation of HIV is well established, the function of SEC in modulating viral latency is less defined and its cell partners are yet to be identified. Results: In this study we identify fused in sarcoma (FUS) as a partner of AFF4 in cells. FUS inhibits the activation of HIV transcription by AFF4 and ELL2, and silences overall HIV gene transcription. Concordantly, depletion of FUS elevates the occupancy of AFF4 and Cdk9 on the viral promoter and activates HIV gene transcription. Live cell imaging demonstrates that FUS co-localizes with AFF4 within nuclear punctuated condensates, which are disrupted upon treating cells with aliphatic alcohol. In HIV infected cells, knockout of FUS delays the gradual entry of HIV into latency, and similarly promotes viral activation in a T cell latency model that is treated with JQ1. Finally, effects of FUS on HIV gene transcription are also exhibited genome wide, where FUS mainly occupies gene promoters at transcription starting sites, while its knockdown leads to an increase in AFF4 and Cdk9 occupancy on gene promoters of FUS affected genes. Conclusions: Towards eliminating the HIV infected reservoir, understanding the mechanisms by which the virus persists in the face of therapy is important. Our observations show that FUS regulates both HIV and global gene transcription and modulates viral latency, thus can potentially serve as a target for future therapy that sets to reactivate HIV from its latent state.
NoteOpen access journal
VersionFinal published version
SponsorsIsrael Science Foundation [755/17]; Ben-Gurion University of the Negev, Israel; National Institute of Health [NS082376]; Office of the Director of the NIH [S10OD013237]; NIH [R21AI127274]
- Super elongation complex promotes early HIV transcription and its function is modulated by P-TEFb.
- Authors: Kuzmina A, Krasnopolsky S, Taube R
- Issue date: 2017 May 27
- A single point mutation in cyclin T1 eliminates binding to Hexim1, Cdk9 and RNA but not to AFF4 and enforces repression of HIV transcription.
- Authors: Kuzmina A, Verstraete N, Galker S, Maatook M, Bensaude O, Taube R
- Issue date: 2014 Jul 1
- Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription.
- Authors: Qi S, Li Z, Schulze-Gahmen U, Stjepanovic G, Zhou Q, Hurley JH
- Issue date: 2017 Jan 30
- FACT Proteins, SUPT16H and SSRP1, Are Transcriptional Suppressors of HIV-1 and HTLV-1 That Facilitate Viral Latency.
- Authors: Huang H, Santoso N, Power D, Simpson S, Dieringer M, Miao H, Gurova K, Giam CZ, Elledge SJ, Zhu J
- Issue date: 2015 Nov 6
- Genome-wide CRISPR knockout screen identifies ZNF304 as a silencer of HIV transcription that promotes viral latency.
- Authors: Krasnopolsky S, Kuzmina A, Taube R
- Issue date: 2020 Sep