Abstract
Comprehensively elucidating the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) latency is a priority to achieve a functional cure. As current 'shock' agents failed to efficiently reactivate the latent reservoir, it is important to discover new targets for developing more efficient latency-reversing agents (LRAs). Here, we found that TRIM28 potently suppresses HIV-1 expression by utilizing both SUMO E3 ligase activity and epigenetic adaptor function. Through global site-specific SUMO-MS study and serial SUMOylation assays, we identified that P-TEFb catalytic subunit CDK9 is significantly SUMOylated by TRIM28 with SUMO4. The Lys44, Lys56 and Lys68 residues on CDK9 are SUMOylated by TRIM28, which inhibits CDK9 kinase activity or prevents P-TEFb assembly by directly blocking the interaction between CDK9 and Cyclin T1, subsequently inhibits viral transcription and contributes to HIV-1 latency. The manipulation of TRIM28 and its consequent SUMOylation pathway could be the target for developing LRAs.
Highlights
Despite the suppressive combined antiretroviral therapy, the persistence of human immunodeficiency virus type 1 (HIV-1) in the latent reservoirs is the major obstacle to achieve a cure (Chun et al, 1997; Finzi et al, 1997; Wong et al, 1997)
We found that a SUMOylation E3 ligase tripartite motifcontaining protein 28 (TRIM28), known as transcriptional intermediary factor 1b (TIF1b) and KAP1 (KRAB-associated protein-1), binds to cyclin-dependent kinase 9 (CDK9) and mediates the SUMOylation of CDK9, resulting in the disassociation of CDK9 with Cyclin T1 and the inhibition of CDK9 kinase activity
To identify cellular targets which may contribute to HIV-1 suppression and latency, we started from the design and high-throughput screening of a custom siRNA library which targeted several cellular pathways within the nucleus including chromatin binding, epigenetic modification, chromatin remodeling, ubiquitination, SUMOylation, and chromosome organization (Supplementary file 1)
Summary
Despite the suppressive combined antiretroviral therapy (cART), the persistence of HIV-1 in the latent reservoirs is the major obstacle to achieve a cure (Chun et al, 1997; Finzi et al, 1997; Wong et al, 1997). To completely eradicate the reservoir, it needs almost 73.4 years of cART due to its long half-life in resting CD4+ T cells (Siliciano et al, 2003). Most of the integration sites locate in the intron of actively transcribed genes (Schroder et al, 2002). Some integration hotspots were found in latently infected clonally expanded CD4+ T cells in HIV-1 patients on cART (Cohn et al, 2015; Maldarelli et al, 2014; Wagner et al, 2014). To decrease the latent reservoirs, several functional cure strategies which are
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
