Cyclosporin A Associated Helicase-Like Protein Facilitates the Association of Hepatitis C Virus RNA Polymerase with Its Cellular Cyclophilin B

Morohashi, Kengo; Sahara, Hiroeki; Watashi, Koichi; Iwabata, Kazuki; Sunoki, Takashi; Kuramochi, Kouji; Takakusagi, Kaori; Miyashita, Hiroki; Sato, Noriyuki; Tanabe, Atsushi; Shimotohno, Kunitada; Kobayashi, Susumu; Sakaguchi, Kengo; Sugawara, Fumio

doi:10.1371/journal.pone.0018285

Cited by 49 publications

(44 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Prior to our finding that DC2 binds m 6 A (Patil et al 2016), DC2 was described as a cellular factor that was necessary for HCV genome replication (Morohashi et al 2011). Recent studies suggest that DC2 enhances the translation of HIF1α mRNA via its helicase function (Tanabe et al 2016).…”

Section: M6a Readersmentioning

confidence: 99%

Rethinking m⁶A Readers, Writers, and Erasers

Meyer

Jaffrey

2017

Annu. Rev. Cell Dev. Biol.

826

872

View full text Add to dashboard Cite

In recent years, m6A has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of m6A residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of m6A are the discovery and characterization of m6A readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of m6A. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early conceptions regarding the reading, writing and erasing of m6A. In this review, we summarize recent advances in m6A research, and we highlight how these new findings have reshaped our understanding of how m6A is regulated in the transcriptome.

show abstract

Section: M6a Readersmentioning

confidence: 99%

Rethinking m⁶A Readers, Writers, and Erasers

Meyer

Jaffrey

2017

Annu. Rev. Cell Dev. Biol.

826

872

View full text Add to dashboard Cite

show abstract

“…Cyclosporin A, an immunosuppressive agent and cyclophillin inhibitor, has been demonstrated to have antiviral activity against HCV replication [28–30]. Therefore, cyclosporin A was tested as an HTA in this study.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of antiviral drug synergy in an infectious HCV system

Lin

Yim

et al. 2016

Antivir ther

View full text Add to dashboard Cite

Background Direct-acting antivirals (DAAs) have greatly improved the treatment of HCV infection. To improve response and prevent resistance, combination regimens have been the focus of clinical development. Regimens are often first assessed in vitro, with most combination studies to date using subgenomic replicon systems, which do not replicate the complete HCV life cycle and preclude study of entry and assembly inhibitors. Infectious full-length HCV systems have been developed and are being used to test drug efficacy. Methods Using cell-based HCV Con1b replicon and an infectious full-length HCV (HCVcc-Luc) infection system, we systematically tested the synergy, additivity or antagonism of combinations of protease, NS5A and nucleotide NS5B inhibitor classes as well as the combination of these DAAs with host-targeting agent cyclosporin A or non-antibody entry inhibitor (S)-chlorcyclizine. Two computational software packages, MacSynergyII and CalcuSyn, were used for data analysis. Results Combinations between different classes showed good consistency across the two viral assay systems and two software platforms. Combinations between NS5A and nucleotide NS5B inhibitors were synergistic, while combinations of protease inhibitors with the other two classes were additive to slightly antagonistic. As expected, combinations of antivirals of the same class were additive. Combination studies between these DAA classes and cyclosporin A or (S)-chlorcyclizine demonstrated additive to synergistic effects and highly synergistic effects, respectively. Combinations of these drugs did not show any added or unexpected cytotoxicity. Conclusions Our results show that in vitro combination studies of anti-HCV DAAs in the HCVcc system may provide useful guidance for drug combination designs in clinical studies. We also demonstrate that these DAAs in combination with host-targeting agents or entry inhibitors may improve HCV treatment response.

show abstract

“…Unless stated otherwise, all manipulations were performed at room temperature according to our protocol described previously [33]. Briefly, a 10 μM of biotinylated pyrenocine B solution was added to a streptavidin-coated 96-well microplate (Thermo fisher scientific, Waltham, MA) and allowed 1 h for immobilization.…”

Section: Phage Display Screeningmentioning

confidence: 99%

“…SPR experiments were performed with a Biacore 3000 system (GE Healthcare UK Ltd., Buckinghamshire, England) according to our protocol described previously [33]. With this system, the molecule of interest (ligand) is immobilized on a sensor surface and the binding partner (analyte) can then be passed over it in a mobile aqueous phase.…”

Section: Spr Analysis Using the Biacore Systemmentioning

confidence: 99%

See 1 more Smart Citation

EpsinR, a target for pyrenocine B, role in endogenous MHC‐II‐restricted antigen presentation

et al. 2014

Self Cite

View full text Add to dashboard Cite

While the presentation mechanism of antigenic peptides derived from exogenous proteins by MHC class II molecules is well understood, relatively little is known about the presentation mechanism of endogenous MHC class II-restricted antigens. We therefore screened a chemical library of 200 compounds derived from natural products to identify inhibitors of the presentation of endogenous MHC class II-restricted antigens. We found that pyrenocine B, a compound derived from the fungus Pyrenochaeta terrestris, inhibits presentation of endogenous MHC class II-restricted minor histocompatibility antigen IL-4 inducible gene 1 (IL4I1) by primary dendritic cells (DCs). Phage display screening and surface plasmon resonance (SPR) analysis were used to investigate the mechanism of suppressive action by pyrenocine B. EpsinR, a target molecule for pyrenocine B, mediates endosomal trafficking through binding of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Lentiviral-mediated short hairpin (sh) RNA downregulation of EpsinR expression in DCs resulted in a decrease in the responsiveness of CD4 + T cells. Our data thus suggest that EpsinR plays a role in antigen presentation, which provides insight into the mechanism of presentation pathway of endogenous MHC class II-restricted antigen.Keywords: Antigen presentation · Epsin R · MHC class II · Pyrenocine B · SNARE Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionExpression of major histocompatibility complex (MHC) class II molecules is restricted to professional antigen-presenting cells (APCs), such as B cells, macrophages, and dendritic cells (DCs), and is essential for peptide presentation to CD4 + T cells. Antigenstimulated CD4 + T cells assist the effector functions of both CD8 + Correspondence: Prof. Hiroeki Sahara e-mail: sahara@azabu-u.ac.jp T cells and B cells. The mechanism underlying the presentation of antigenic peptides derived from exogenous proteins by MHC class II molecules is relatively well understood [1]. Several biochemical studies have revealed that a large fraction of naturally processed peptides presented by MHC II molecules are derived from endogenous cytoplasmic and nuclear proteins [2][3][4][5][6].Two different pathways have been implicated in the processing of these antigens, with one pathway involving the cytoplasmic proteasome [7][8][9] and another involving autophagy [5,[10][11][12]. As an example of a proteasome-dependent pathway, the presentation by HLA-DR4 of the endogenous protein glutamate decarboxylase, a C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 3220-3231 Antigen processing 3221 self-antigen closely related to insulin-dependent diabetes mellitus, requires proteasomal and calpain activity [7]. Likewise, influenza virus-infected primary DCs present antigenic peptides in the context of MHC class II molecules via a proteasome/TAP pathway [9]. Autophagic pathways are also involved in endog...

show abstract

Cyclosporin A Associated Helicase-Like Protein Facilitates the Association of Hepatitis C Virus RNA Polymerase with Its Cellular Cyclophilin B

Cited by 49 publications

References 36 publications

Rethinking m⁶A Readers, Writers, and Erasers

Rethinking m⁶A Readers, Writers, and Erasers

Evaluation of antiviral drug synergy in an infectious HCV system

EpsinR, a target for pyrenocine B, role in endogenous MHC‐II‐restricted antigen presentation

Contact Info

Product

Resources

About

Cyclosporin A Associated Helicase-Like Protein Facilitates the Association of Hepatitis C Virus RNA Polymerase with Its Cellular Cyclophilin B

Cited by 49 publications

References 36 publications

Rethinking m6A Readers, Writers, and Erasers

Rethinking m6A Readers, Writers, and Erasers

Evaluation of antiviral drug synergy in an infectious HCV system

EpsinR, a target for pyrenocine B, role in endogenous MHC‐II‐restricted antigen presentation

Contact Info

Product

Resources

About

Rethinking m⁶A Readers, Writers, and Erasers

Rethinking m⁶A Readers, Writers, and Erasers