TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb

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.

DNA dependent protein kinase (DNA-PK) enhances HIV transcription by promoting RNA polymerase II activity and recruitment of transcription machinery at HIV LTR

“…Pertaining HIV transcription, the role of TRIM28 is still not clear. However, the presence of TRIM28 bound with 7SK snRNP complex at HIV LTR has been documented [42], and the role of TRIM28 during HIV latency has also been proposed [43]. In addition to ours [16], other studies have also noted the interaction between RNAP II and DNA-PK [44].…”

“…This modification converts TRIM28 from a transcriptionally repressive factor to a transcriptionally active factor [37-39]. It has been recently documented that TRIM28 potently suppresses HIV-1 expression by utilizing both SUMO E3 ligase activity and epigenetic adaptor function [43]. We hypothesized that if DNA-PK plays a major role in TRIM28 activation by catalyzing its phosphorylation at serine 824, then DNA-PK inhibition or depletion in cells should reduce TRIM28 phosphorylation and thus contribute to the suppression of HIV gene repression, observed upon ablation of DNA-PK.…”

Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

“…Moreover, they further highlight the cell type specific mechanism of action of the repressors involved in viral latency. CTIP2 and KAP1 are highly expressed in resting T cells and depleted upon activation (31,56). In addition, increased levels of CTIP2 are associated with persistence of HIV-1 latency in the brain (14) and increased level of KAP1 in the peripheral blood of gastric cancer patients is a biomarker predicting cancer stage progression (57)(58)(59)(60).…”

“…More recently, the restriction factor APOBEC3A (Apolipoprotein B mRNA-Editing enzyme Catalytic polypeptide-like 3G) has been described to recruit KAP1 to suppress HIV-1 transcription (30). In addition, a very recent study suggests that KAP1 represses HIV-1 gene expression by mediating CDK9 SUMOylation resulting in P-TEFb repression in T cells (31). Surprisingly, since KAP1 functions have been extensively studied in T lineage, nothing has been done to define its role and its mechanism of action on HIV-1 infection in myeloid cells.…”

SUMO2/3 participates in regulating the protective effect of propofol on human umbilical vein endothelial cells

“…For example, SUMO modification of lbd30 by six1 regulates secondary cell wall formation in Arabidopsis thaliana [28]. Trim28 prolongs HIV-1 latency by promoting SUMO modification of CDK9 and inhibiting p-tefb [29]. To determine the expression of SUMO2 and SUMO3, qRT-PCR and Western blotting were performed.…”