Nuclear and cytosolic JNK signalling in neurons

Coffey, Eleanor T.

doi:10.1038/nrn3729

Cited by 286 publications

(296 citation statements)

References 191 publications

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“…MAPKs regulate a number of cellular functions, such as gene expression, cell differentiation, proliferation, and death. JNK is important for cell stress responses, cellular apoptosis pathways, and inflammatory responses (52,53). Two EBV immediate early proteins, BZLF1 and BRFL1, and two latent proteins, LMP1 and LMP2, have previously been shown to activate JNK (9,17,22), and BZLF1, BRLF1, and LMP1 have also been reported to activate p38 (22,37).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Liu

Cohen

2016

J Virol

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IMPORTANCE Epstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency. E pstein-Barr virus (EBV) is a cause of infectious mononucleosis and is associated with both B lymphocyte and epithelial cell malignancies. EBV encodes a number of proteins that trigger cell signaling pathways, such as AP-1, JAK-STAT, NF-B, and phosphatidylinositol 3-kinase (PI3K)/Akt, which are critical for cell survival, virus latency, and growth transformation (1-6). For example, EBV latent membrane protein 1 (LMP1) mimics CD40 signaling and is important for EBV-induced B cell growth proliferation, inhibition of apoptosis, and EBV transformation. LMP1 interacts with tumor necrosis factor receptor-associated factors (TRAFs), leading to activation of NF-B, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), PI3K/Akt, and STAT3 (7-12). EBV LMP2A mimics B cell receptor signaling and contributes to the long-term survival of B cells (13-16). LMP2A activates extracellular signal-related protein kinase (ERK), PI3K/Akt, and JNK (17) and downregulates NF-B and STAT signaling pathways (18). The EBV immediate early protein BZLF1 activates virus reactivation from latency (19-21). BZLF1 activates p38 and JNK to turn on the ATF2 transcription factor (22). BRLF1, another EBV immediate early protein, activates the AP-1 pathway by increasing the levels of phosphorylated p38, JNK, and ERK (22, 23) and induces phosphorylation of Akt through the PI3K pathway (24). Activation of Akt, ERK, and p38 signaling is required for EBV reactivation from latency (25-28).To identify additional EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 promoter activity in AP-1-luciferase reporter assays. We found that the EBV tegument protein BGLF2 induced AP-1 reporter activity and activated p38 and JNK. BGLF2 promoted EBV reactivation by enhancing BZLF1 expression and EBV production, and p38 activation by BGLF2 was required for these activities. Citation Liu X, Cohen JI. 2016. Epstein-Barr virus (EBV) tegument protein BGLF2 promotes EBV reactivation through activation of the p38 mitogen-activated protein kinase.

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Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Liu

Cohen

2016

J Virol

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“…This and other triggers, such as withdrawal of trophic support, axotomy, and heat shock, are known inducers of c-Jun N-terminal kinase (JNK) signaling. In most cells, JNKs play an important role in stress response pathways, but in neurons they also control dendritic arborization and synaptic plasticity (24). In response to nerve injury, JNKs are redirected through mobilization of JNKinteracting protein 3 (JIP3) and dual-leucine-zipper kinase (DLK).…”

Section: Co-option Of a Neuronal Stress Pathway For Phase I Of Reactimentioning

confidence: 99%

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

Cliffe

Wilson

2017

J Virol

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Herpes simplex virus (HSV) establishes a latent reservoir in neurons of human peripheral nerves. In this quiescent state, the viral genome persists as a circular, histone-associated episome, and transcription of viral lytic cycle genes is largely suppressed through epigenetic processes. Periodically, latent virus undergoes reactivation whereby lytic genes are activated and viral replication occurs. In this Gem, we review recent evidence that mechanisms governing the initial transcription of lytic genes are distinct from those of de novo infection and directly link reactivation to neuronal stress response pathways. We also discuss evidence that lytic cycle gene expression can be uncoupled from the full reactivation program, arguing for a less sharply bimodal definition of latency.

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“…Signaling by the JNKs has been intensely studied for more than 2 decades, with several previous reviews covering general aspects (1) or some covering more specific aspects, such as JNK signaling in the brain or the opportunities for inhibition of JNK signaling as a therapeutic strategy in cancer (2,3). Indeed, JNKs have attracted attention as potential pharmaceutical targets through their implication via biochemical, cellular, and systemslevel approaches in disease development (4,5).…”

mentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

409

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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Nuclear and cytosolic JNK signalling in neurons

Cited by 286 publications

References 191 publications

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

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