Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators

Sarkar, Roni; Verma, Subhash C.

doi:10.18632/oncotarget.20648

Cited by 7 publications

(4 citation statements)

References 101 publications

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“…In the non-human primate model of neuroHIV, we have previously demonstrated that a decrease in Egr-1 expression in neurons is associated with neurological deficits in the context of inflammation (63). Its role in cell transcriptional regulation has been described (64). IRF4, on the other hand, is a positive regulator of inflammation (65, 66), converge as a common epigenetic switch.…”

Section: Discussionmentioning

confidence: 99%

Modeling the Function of TATA Box Binding Protein in Transcriptional Changes Induced by HIV-1 Tat in Innate Immune Cells and the Effect of Methamphetamine Exposure

et al. 2019

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Innate immune cells are targets of HIV-1 infection in the Central Nervous System (CNS), generating neurological deficits. Infected individuals with substance use disorders as co-morbidities, are more likely to have aggravated neurological disorders, higher CNS viral load and inflammation. Methamphetamine (Meth) is an addictive stimulant drug, commonly among HIV+ individuals. The molecular basis of HIV direct effects and its interactions with Meth in host response, at the gene promoter level, are not well understood. The main HIV-1 peptide acting on transcription is the transactivator of transcription (Tat), which promotes replication by recruiting a Tata-box binding protein (TBP) to the virus long-terminal repeat (LTR). We tested the hypothesis that Tat can stimulate host gene expression through its ability to increase TBP, and thus promoting its binding to promoters that bear Tata-box binding motifs. Genes with Tata-box domains are mainly inducible, early response, and involved in inflammation, regulation and metabolism, relevant in HIV pathogenesis. We also tested whether Tat and Meth interact to trigger the expression of Tata-box bearing genes. The THP1 macrophage cell line is a well characterized innate immune cell system for studying signal transduction in inflammation. These cells are responsive to Tat, as well as to Meth, by recruiting RNA Polymerase (RNA Pol) to inflammatory gene promoters, within 15 min of stimulation (1). THP-1 cells, including their genetically engineered derivatives, represent valuable tools for investigating monocyte structure and function in both health and disease, as a consistent system (2). When differentiated, they mimic several aspects of the response of macrophages, and innate immune cells that are the main HIV-1 targets within the Central Nervous System (CNS). THP1 cells have been used to characterize the impact of Meth and resulting neurotransmitters on HIV entry (1), mimicking the CNS micro-environment. Integrative consensus sequence analysis in genes with enriched RNA Pol, revealed that TBP was a major transcription factor in Tat stimulation, while the co-incubation with Meth shifted usage to a distinct and diversified pattern. For validating these findings, we engineered a THP1 clone to be deficient in the expression of all major TBP splice variants, and tested its response to Tat stimulation, in the presence or absence of Meth. Transcriptional patterns in TBP-sufficient and deficient clones confirmed TBP as a dominant transcription factor in Tat stimulation, capable of inducing genes with no constitutive expression. However, in the presence of Meth, TBP was no longer necessary to activate the same genes, suggesting promoter plasticity. These findings demonstrate TBP as mechanism of host-response activation by HIV-1 Tat, and suggest that promoter plasticity is a challenge imposed by co-morbid factors such as stimulant drug addiction. This may be one mechanism responsible for limited efficacy of therapeutic approaches in HIV+ Meth abusers.

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Section: Discussionmentioning

confidence: 99%

Modeling the Function of TATA Box Binding Protein in Transcriptional Changes Induced by HIV-1 Tat in Innate Immune Cells and the Effect of Methamphetamine Exposure

et al. 2019

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“…Kirsten rat sarcoma viral oncogene homolog (KRAS) upregulates RTA expression through the rapidly-accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MEK)/ERK pathway [ 88 ]. Early growth response protein 1 (EGR1), a phosphorylation target of the p38 pathway, binds to and promotes transcriptional activity at the RTA promoter [ 89 ]. Through regulation of RTA, the host MAPK signaling pathways function as key triggers of the KSHV lytic cycle.…”

Section: Mechanisms Regulating Kshv Reactivation From Latencymentioning

confidence: 99%

Regulation of KSHV Latency and Lytic Reactivation

Broussard

Damania

2020

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle—latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target.

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“…Previous studies suggested a role for CBP/p300 in modulating the RTA promoter activity (Gwack et al, 2001) and since EGR1 has a specific binding site for CBP/p300 it was speculated that EGR1 and CBP/p300 could be working cooperatively to regulate RTA activity. EGR1 was not essential to activate the RTA promoter however, expression of EGR1 significantly enhanced activation of the RTA promoter thus suggesting that EGR1 can regulate the transcriptional activities of CBP/p300 (Sarkar and Verma, 2017). These results suggest a potential role for EGR1 as a key regulator for KSHV lytic reactivation.…”

Section: Herpesviridaementioning

confidence: 83%

“…EGR1 has also been found to regulate the replication and transcription activator (RTA) gene, which regulates the switch from latent to lytic replication during KSHV infection (Dyson et al, 2010(Dyson et al, , 2012. Loss of EGR1 via small interfering RNA (siRNA) resulted in decreased virion production following lytic reactivation (Sarkar and Verma, 2017) suggesting a pro-viral role for EGR1 during KSHV infections. Previous studies suggested a role for CBP/p300 in modulating the RTA promoter activity (Gwack et al, 2001) and since EGR1 has a specific binding site for CBP/p300 it was speculated that EGR1 and CBP/p300 could be working cooperatively to regulate RTA activity.…”

Section: Herpesviridaementioning

confidence: 99%

Examining the role of EGR1 during viral infections

Lehman

Kehn-Hall

2022

Front. Microbiol.

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Early growth response 1 (EGR1) is a multifunctional mammalian transcription factor capable of both enhancing and/or inhibiting gene expression. EGR1 can be activated by a wide array of stimuli such as exposure to growth factors, cytokines, apoptosis, and various cellular stress states including viral infections by both DNA and RNA viruses. Following induction, EGR1 functions as a convergence point for numerous specialized signaling cascades and couples short-term extracellular signals to influence transcriptional regulation of genes required to initiate the appropriate biological response. The role of EGR1 has been extensively studied in both physiological and pathological conditions of the adult nervous system where it is readily expressed in various regions of the brain and is critical for neuronal plasticity and the formation of memories. In addition to its involvement in neuropsychiatric disorders, EGR1 has also been widely examined in the field of cancer where it plays paradoxical roles as a tumor suppressor gene or oncogene. EGR1 is also associated with multiple viral infections such as Venezuelan equine encephalitis virus (VEEV), Kaposi’s sarcoma-associated herpesvirus (KSHV), herpes simplex virus 1 (HSV-1), human polyomavirus JC virus (JCV), human immunodeficiency virus (HIV), and Epstein–Barr virus (EBV). In this review, we examine EGR1 and its role(s) during viral infections. First, we provide an overview of EGR1 in terms of its structure, other family members, and a brief overview of its roles in non-viral disease states. We also review upstream regulators of EGR1 and downstream factors impacted by EGR1. Then, we extensively examine EGR1 and its roles, both direct and indirect, in regulating replication of DNA and RNA viruses.

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Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators

Cited by 7 publications

References 101 publications

Modeling the Function of TATA Box Binding Protein in Transcriptional Changes Induced by HIV-1 Tat in Innate Immune Cells and the Effect of Methamphetamine Exposure

Modeling the Function of TATA Box Binding Protein in Transcriptional Changes Induced by HIV-1 Tat in Innate Immune Cells and the Effect of Methamphetamine Exposure

Regulation of KSHV Latency and Lytic Reactivation

Examining the role of EGR1 during viral infections

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