EZH2 phosphorylation regulates Tat‐induced HIV‐1 transactivation via ROS/Akt signaling pathway

Abstract

Edited by Ivan Sadowski Keywords:HIV-1 Enhancer of zeste homolog 2 Reactive oxygen species AKT a b s t r a c t EZH2 plays a major role in HIV-1 latency, however, the molecular linkage between Tat-induced HIV-1 transactivation and EZH2 activity is not fully understood. It was shown Tat induced HIV-1 transactivation through inhibiting EZH2 activity. Tat decreased the levels of H3K27me3 and EZH2 occupy at the long terminal repeat (LTR) of HIV-1. We further showed for the first time that transfected with Tat construct resulted in an increase in phosphorylated EZH2 (p-EZH2), mediated by active Akt. ROS/Akt-dependent p-EZH2 was correlated with Tat-induced transactivation. Our study reveals that novel mechanisms allow Tat-induced HIV-1 transactivation by ROS/Akt-dependent downregulating the EZH2 epigenetic silencing machinery.

Visualization of HIV-1 RNA Transcription from Integrated HIV-1 DNA in Reactivated Latently Infected Cells

“…Experiments were carried out with J1.1 cells, which, unlike JLat 10.6 cells, produce infectious virus after reactivation with LRAs [ 30 ]. We tested the reactivation of J1.1 cells using the following LRAs or combinations of LRAs for 8 h: (1) TNF-α; (2) PMA/I [ 41 , 42 ], (3) FK228 (romidepsin, a histone deacetylase inhibitor) [ 43 , 44 ], (4) FK228 with JQ1 (a bromodomain and extra-terminal motif (BET) inhibitor) [ 45 , 46 , 47 ], and (5) FK228 with DZNep (a histone methyltransferase inhibitor) [ 48 , 49 ] ( Figure 2 ). Following reactivation, cells were imaged for unspliced vRNA, vDNA, and Gag protein [ 32 , 33 ].…”

A NIR-responsive indocyanine green-genistein nanoformulation to control the polycomb epigenetic machinery for the efficient combinatorial photo/chemotherapy of glioblastoma

“…Moreover, the increased ROS stress in the context of the DZNepmediated depletion of EZH2 and H3K27me3 in acute myeloid leukemia has already been reported. 63,64 BMI-1 is functionally linked to the oxidative metabolism of cancer cells and confers resistance to oxidative stress and downregulation promotes a damaging effect. Taken together these results indicate the role of the PRC subunits in the regulation of the cellular stress mechanism.…”

Epigenetic regulation of HIV-1 latency: focus on polycomb group (PcG) proteins

“…In HIV-1 latent reservoir, particularly in resting CD4+ T cell, the silencing of HIV-1 gene expression has been linked to the increased expression of EZH2. Their activities are upregulated by different mechanism such as signaling pathway, post-transcriptional modifications, highly reactive oxygen species, miRNA, and transcriptional factors; while on the other hand, they are downregulated by Akt signaling pathway which inhibits EZH2 activities and thus reactivate the HIV-1 from latency [ 130 , 131 ]. Further, the presence of histone lysine methyltransferase component of PRC2 (EZH2) and Suv39h1 plays a unique role in the HIV-1 gene silencing.…”

“…In resting CD4+ T cells, the EZH2, a component of PRC2 is associated with H3K27me3 and thus enhances HIV-1 latency and so the activity of EZH2 can be regulated by Akt. Activation of Akt signaling phosphorylates EZH2 and inhibits its enzymatic activity, thus releasing the epigenetic silencing of HIV-1 promoter [ 193 , 194 ]. In contrast to non-PIs, the administration of PIs during shock-and-kill strategies may enhance HIV-1 latency by blocking Akt signaling, and so, it increases the enzymatic activity of EZH2 (Fig.…”