Acute Infection of Sindbis Virus Induces Phosphorylation and Intracellular Translocation of Small Heat Shock Protein HSP27 and Activation of p38 MAP Kinase Signaling Pathway

Nakatsue, Takeo; Katoh, Iyoko; Nakamura, Satoru; Takahashi, Yoshie; Ikawa, Yoji; Yoshinaka, Yoshiyuki

doi:10.1006/bbrc.1998.9724

Cited by 40 publications

(26 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has been shown for many RNA viruses, including the alphavirus SINV, which was reported to induce the activation of p38 MAPK and also the phosphorylation of HSP27 (heat shock protein 27), one of its substrates (56). For Japanese encephalitis virus (JEV), the unfolded protein response (UPR), triggered by excess viral protein synthesis in the endoplasmic reticulum, results in eventual apoptosis, mediated in a p38 MAPK-dependent manner (57).…”

Section: Discussionmentioning

confidence: 95%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

116

103

View full text Add to dashboard Cite

Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a highthroughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections. C hikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease spread by Aedes mosquitoes and characterized by a sudden onset of febrile illness, nausea, headache, and most importantly, severe and persistent musculoskeletal pain (1). It reemerged in tropical Asia and Africa 1 decade ago and since 2013 has infected more than 1.5 million people in the Americas (2). So far, no licensed vaccine or antiviral treatment exists to counter this disease. Over the years, many research groups have focused on...

show abstract

Section: Discussionmentioning

confidence: 95%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

116

103

View full text Add to dashboard Cite

show abstract

“…An increasing amount of information has demonstrated that many viruses activate the p38 MAPK pathway to augment their efficient replication (51)(52)(53)(54)(55). To this end, although in our earlier study we have demonstrated that p38 MAPK activation is beneficial for ARV replication (31), its precise role in regulating ARV entry and replication remains elusive so far.…”

Section: Discussionmentioning

confidence: 96%

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Huang

Wang

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Very little is known about the mechanism of cell entry of avian reovirus (ARV). The aim of this study was to explore the mechanism of ARV entry and subsequent infection. Cholesterol mainly affected the early steps of the ARV life cycle, because the presence of cholesterol before and during viral adsorption greatly blocked ARV infectivity. Although we have demonstrated that ARV facilitating p38 MAPK is beneficial for virus replication, its mechanism remains unknown. Here, we show that ARV-induced phosphorylation of caveolin-1 (Tyr 14 ), dynamin-2 expression, and Rac1 activation through activation of p38 MAPK and Src in the early stage of the virus life cycle is beneficial for virus entry and productive infection. The strong inhibition by dynasore, a specific inhibitor of dynamin-2, and depletion of endogenous caveolin-1 or dynamin-2 by siRNAs as well as the caveolin-1 colocalization study implicate caveolin-1-mediated and dynamin-2-dependent endocytosis as a significant avenue of ARV entry. By means of pharmacological inhibitors, dominant negative mutants, and siRNA of various cellular proteins and signaling molecules, phosphorylation of caveolin-1, dynamin-2 expression, and Rac1 activation were suppressed, suggesting that by orchestrating p38 MAPK, Src, and Rac1 signaling cascade in the target cells, ARV creates an appropriate intracellular environment facilitating virus entry and productive infection. Furthermore, disruption of microtubules, Rab5, or endosome acidification all inhibited ARV infection, suggesting that microtubules and small GTPase Rab5, which regulate transport to early endosome, are crucial for survival of ARV and that exposure of the virus to acidic pH is required for productive infection.

show abstract

“…Because they reorganize or utilize various cellular functions, it seems likely that viruses would take advantage of pre-existing signalling pathways to induce cellular and/or viral gene expression to promote virus replication. Recent reports have shown that several viruses can induce the activation of MAPK pathways in infected cells, such as human immunodeficiency virus type 1 (Kumar et al, 1998;Li et al, 1997), human cytomegalovirus (Rodems & Spector, 1998), echovirus (Huttunen et al, 1998), Sindbis virus (Nakatsue et al, 1998) and herpes simplex virus type 1 (HSV-1) (McLean & Bachenheimer, 1999;Zachos et al, 1999). However, the precise role of MAPK in the replication of viruses remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Replication of varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation

Rahaus

Desloges

Wolff

2004

Journal of General Virology

View full text Add to dashboard Cite

Stimulation of the Jun NH 2 -terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase (p38/MAPK) is part of the stress-related signal transduction pathways conveying signals from the cell surface into the nucleus in order to initiate programmes of gene expression. Here, it was shown that infection by varicella-zoster virus (VZV) caused a 34-fold increase in activation of JNK/SAPK in the early phase of infection and a 2-fold increase in activation of p38/MAPK in the later phase. The phosphorylation of downstream targets c-Jun and ATF-2 was also increased; subsequent cascades to induce pro-inflammatory responses were significantly activated whereas cascades to activate apoptotic events were not. In the late phase of infection, both JNK/SAPK and p38/MAPK activities were reduced to basal levels. The use of specific inhibitors demonstrated that inhibition of JNK/SAPK resulted in a 2-fold increase in VZV replication whereas a strong decrease in virus replication was observed after inhibition of p38/MAPK. In contrast, constitutive activation of JNK/SAPK resulted in a decline in VZV replication. Blocking gene expression by treating cells with actinomycin D or cycloheximide prior to infection resulted in activation of neither JNK/SAPK nor p38/MAPK. It was assumed that the presence of tegument proteins was not sufficient to activate stress pathways, but that expression of viral genes was necessary. This suggests that activation of stress pathways by VZV infection represents a finely regulated system that activates cellular transcription factors for transregulation of VZV-encoded genes, but prevents activation of cellular defence mechanisms.

show abstract

Acute Infection of Sindbis Virus Induces Phosphorylation and Intracellular Translocation of Small Heat Shock Protein HSP27 and Activation of p38 MAP Kinase Signaling Pathway

Cited by 40 publications

References 0 publications

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Replication of varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation

Contact Info

Product

Resources

About