HIV-1 Tat potently stabilises Mdm2 and enhances viral replication

Raja, Rameez; Ronsard, Larance; Lata, Sneh; Trivedi, Shubhendu; Banerjea, Akhil C.

doi:10.1042/bcj20160825

Cited by 24 publications

(34 citation statements)

References 67 publications

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“…An siRNA screen based on the most differentially expressed genes from our transcriptomic analysis in virus-infected MDMs further revealed that MDM2 acts as one of the rare positive regulators of HIV-1 infection in this cell type (9). Some previous studies performed with immortalized cell lines have shown that MDM2 can regulate HIV-1 infection by interacting with viral proteins such as Tat and Vif (21,22,34). However, our results suggest that MDM2 can shape the cellular environment by itself, thereby affecting the susceptibility of MDMs to productive HIV-1 infection.…”

Section: Discussionmentioning

confidence: 70%

Expression of MDM2 in Macrophages Promotes the Early Postentry Steps of HIV-1 Infection through Inhibition of p53

Breton

Desrosiers

Ouellet

et al. 2019

J Virol

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The molecular basis for HIV-1 susceptibility in primary human monocyte-derived macrophages (MDMs) was previously evaluated by comparing the transcriptome of infected and bystander populations. Careful analysis of the data suggested that the ubiquitin ligase MDM2 acted as a positive regulator of HIV-1 replication in MDMs. In this study, MDM2 silencing through transcript-specific small interfering RNAs in MDMs induced a reduction in HIV-1 reverse transcription and integration along with an increase in the expression of p53-induced genes, including CDKN1A. Experiments with Nutlin-3, a pharmacological inhibitor of MDM2 p53-binding activity, showed a similar effect on HIV-1 infection, suggesting that the observed restriction in HIV-1 production results from the release/activation of p53 and not the absence of MDM2 per se. Knockdown and inhibition of MDM2 also both correlate with a decrease in the Thr592-phosphorylated inactive form of SAMHD1. The expression level of MDM2 and the p53 activation status are therefore important factors in the overall susceptibility of macrophages to HIV-1 infection, bringing a new understanding of signaling events controlling the process of virus replication in this cell type. IMPORTANCE Macrophages, with their long life span in vivo and their resistance to HIV-1-mediated cytopathic effect, might serve as viral reservoirs, contributing to virus persistence in an infected individual. Identification of host factors that increase the overall susceptibility of macrophages to HIV-1 might provide new therapeutic targets for the efficient control of viral replication in these cells and limit the formation of reservoirs in exposed individuals. In this study, we demonstrate the importance of p53 regulation by MDM2, which creates a cellular environment more favorable to the early steps of HIV-1 replication. Moreover, we show that p53 stabilization reduces virus infection in human macrophages, highlighting the important role of p53 in antiviral immunity.

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Section: Discussionmentioning

confidence: 70%

Expression of MDM2 in Macrophages Promotes the Early Postentry Steps of HIV-1 Infection through Inhibition of p53

Breton

Desrosiers

Ouellet

et al. 2019

J Virol

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“…Tat is also ubiquitinated through Lys-63-linked ubiquitin chains for enhancing its transcriptional activity (41). Lys-63-linked Tat ubiquitination is also carried out by cellular E3 ubiquitin ligase, MDM2, and Tat translocates MDM2 into the nucleus to protect it from proteasomal degradation (42). Tat also uses MDM2 for suppressing immune activation by promoting IRF-1 degradation (34).…”

Section: Discussionmentioning

confidence: 99%

The host cell ubiquitin ligase protein CHIP is a potent suppressor of HIV-1 replication

Ali

Farooqui

Banerjea

2019

Journal of Biological Chemistry

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Edited by Charles E. Samuel Human immunodeficiency virus-1 (HIV-1) Tat is degraded in the host cell both by proteasomal and lysosomal pathways, but the specific molecules that engage with Tat from these pathways are not known. Because E3 ubiquitin ligases are the primary determinants of substrate specificity within the ubiquitin-dependent proteasomal degradation of proteins, we first sought to identify the E3 ligase associated with Tat degradation. Based on the intrinsic disordered nature of Tat protein, we focused our attention on host cell E3 ubiquitin ligase CHIP (C terminus of HSP70-binding protein). Co-transfection of Tat with a CHIPexpressing plasmid decreased the levels of Tat protein in a dosedependent manner, without affecting the corresponding mRNA levels. Additionally, the rate of Tat protein degradation as measured by cycloheximide (CHX) chase assay was increased in the presence of CHIP. A CHIP mutant lacking the U-box domain, which is responsible for protein ubiquitination (CHIP⌬U-box), was unable to degrade Tat protein. Furthermore, CHIP promoted ubiquitination of Tat by both WT as well as Lys-48ubiquitin, which has only a single lysine residue at position 48. CHIP transfection in HIV-1 reporter TZM-bl cells resulted in decreased Tat-dependent HIV-1 long-terminal repeat (LTR) promoter transactivation as well as HIV-1 virion production. CHIP knockdown in HEK-293T cells using CRISPR-Cas9 led to higher virion production and enhanced Tat-mediated HIV-1 LTR promoter transactivation, along with stabilization of Tat protein. Together, these results suggest a novel role of host cell E3 ubiquitin ligase protein CHIP in regulating HIV-1 replication through ubiquitin-dependent degradation of its regulatory protein Tat.

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“…Western blot analysis was performed as described earlier 28 , 29 . The primary antibodies used were anti-AKT, anti-S473 phopsho-AKT, anti-GAPDH, anti-PARP, anti-Caspase-3, anti-ERK1/2, anti-phospho 44/42 ERK1/2, anti-phospho-SAPK/JNK, anti-SAPK/JNK, anti-SP1, anti-LC3B (Cell Signalling Technology), anti-p24 (Cat No.…”

Section: Methodsmentioning

confidence: 99%

Serum deprivation/starvation leads to reactivation of HIV-1 in latently infected monocytes via activating ERK/JNK pathway

Raja

Lata

Trivedi

et al. 2018

Sci Rep

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Despite the high success rate, antiretroviral therapy does not cure the disease completely due to presence of latent viral reservoirs. Although several studies have addressed this issue earlier, the role of serum starvation/deprivation in HIV-1 latency has not been studied. So, we investigated the role of serum starvation in regulating HIV-1 latency. The impact of serum starvation on HIV-1 latency was assessed in latently infected monocytes U1 and T-cells J1.1. Serum starvation breaks HIV-1 latency in U1 cells. Under similar conditions, J1.1 cells failed to show reactivation of virus. We investigated the involvement of cell death pathway and autophagy during the serum starvation in viral reactivation. Inhibition of these pathways did not affect viral reactivation. Furthermore, other crucial factors like NF-κB, SP1 and AKT did not play any role in regulating viral latency. Here, we report that serum deprivation up-regulates ERK/JNK pathway. This leads to phosphorylation of c-Jun which plays an important role in viral reactivation. Treatment of cells with U0126, an ERK kinase inhibitor, potently inhibited viral replication. In summary, we show that serum starvation leads to reactivation of HIV-1 in latently infected monocytes through the ERK/JNK pathway.

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HIV-1 Tat potently stabilises Mdm2 and enhances viral replication

Cited by 24 publications

References 67 publications

Expression of MDM2 in Macrophages Promotes the Early Postentry Steps of HIV-1 Infection through Inhibition of p53

Expression of MDM2 in Macrophages Promotes the Early Postentry Steps of HIV-1 Infection through Inhibition of p53

The host cell ubiquitin ligase protein CHIP is a potent suppressor of HIV-1 replication

Serum deprivation/starvation leads to reactivation of HIV-1 in latently infected monocytes via activating ERK/JNK pathway

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