Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90

Okamoto, Tomoyoshi; Nishimura, Yorihiro; Ichimura, Tsuyoshi; Suzuki, Kensuke; Miyamura, Tatsuo; Suzuki, Tetsuro; Moriishi, Kohji; Matsuura, Yoshiharu

doi:10.1038/sj.emboj.7601367

Cited by 225 publications

(163 citation statements)

References 53 publications

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“…Therefore, another component downstream of PI3K-Akt in the mTOR pathway might be targeted by NS5A. Our previously published results show that the domain I region of NS5A associated with cellular protein FKBP38 (27), which was further confirmed by the claims of another research group that NS5A bound to the 3ϫTPR region of FKBP38 (36). Recent researches have discovered that FKBP38 was a new member of the mTOR pathway and an intrinsic antagonist for mTOR activity (31).…”

Section: Discussionsupporting

confidence: 56%

“…This suggested that FKBP38 played a role in tuberous sclerosis complex-mediated tumor inhibition. Furthermore, FKBP38 has been suggested to be involved in promoting HCV replication via formation of a triple complex with HCV NS5A and Hsp90 (36). These data suggested that FKBP38 might play important roles in HCV infection and pathogenesis.…”

Section: Discussionmentioning

confidence: 69%

“…Because of our previous finding that NS5A interacted with FKBP38 (27) and the recent discovery that FKBP38 was a new member in the mTOR pathway and an intrinsic antagonist for mTOR activity (31, 32), we thus investigated whether the mTOR pathway activation by NS5A was dependent on the NS5A-FKBP38 association. For this purpose, plasmids encoding wild type NS5A, wild type FKBP38, a NS5A mutant without FKBP38-binding region (NS5A-⌬I), or a FKBP38 mutant without the NS5A binding region (FKBP38-⌬3ϫTPR) (27,36) (Fig. 2A) was transfected alone or cotransfected into Huh7 cells FIGURE 1.…”

Section: Resultsmentioning

confidence: 99%

“…These results clearly demonstrated that up-regulation of mTOR activity by NS5A was due to the impairment of mTOR-FKBP38 binding by the NS5A-FKBP38 association. It was important to note that the sites of FKBP38 responsible for binding to NS5A and mTOR were localized in two distinct regions (31,36). Therefore, the question arose as to why NS5A, FKBP38, and mTOR were unable to form a triple complex.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C Virus NS5A Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Contributing to Cell Survival by Disrupting the Interaction between FK506-binding Protein 38 (FKBP38) and mTOR

Lü

Dong

Tong

et al. 2010

Journal of Biological Chemistry

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Hepatitis C virus (HCV) often establishes a persistent infection that most likely involves a complex host-virus interplay. We previously reported that the HCV nonstructural protein 5A (NS5A) bound to cellular protein FKBP38 and resulted in apoptosis suppression in human hepatoma cell line Huh7. In the present research we further found that NS5A increased phosphorylation levels of two mTOR-targeted substrates, S6K1 and 4EBP1, in Huh7 in the absence of serum. mTOR inhibitor rapamycin or NS5A knockdown blocked S6K1 and 4EBP1 phosphorylation increase in NS5A-Huh7 and HCV replicon cells, suggesting that NS5A specifically regulated mTOR activation. Overexpression of NS5A and FKBP38 mutants or FKBP38 knockdown revealed this mTOR activation was dependent on NS5A-FKBP38 interaction. Phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 treatment in NS5A-Huh7 showed that the mTOR activation was independent of PI3K. Moreover, NS5A suppressed caspase 3 and poly(ADP-ribose) polymerase activation, which was abolished by NS5A knockdown or rapamycin, indicating NS5A inhibited apoptosis specifically through the mTOR pathway. Further analyses suggested that apoptotic inhibition exerted by NS5A via mTOR also required NS5A-FKBP38 interaction. Glutathione S-transferase pulldown and co-immunoprecipitation showed that NS5A disrupted the mTOR-FKBP38 association. Additionally, NS5A or FKBP38 mutants recovered the mTOR-FKBP38 interaction; this indicated that the impairment of mTOR-FKBP38 association was dependent on NS5A-FKBP38 binding. Collectively, our data demonstrate that HCV NS5A activates the mTOR pathway to inhibit apoptosis through impairing the interaction between mTOR and FKBP38, which may represent a pivotal mechanism for HCV persistence and pathogenesis.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Hepatitis C Virus NS5A Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Contributing to Cell Survival by Disrupting the Interaction between FK506-binding Protein 38 (FKBP38) and mTOR

Lü

Dong

Tong

et al. 2010

Journal of Biological Chemistry

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“…Some of these proteins, such as hVAP-33 (41), FKBP8 (44), Hsp90 (40,44), and cyclophilin A (39), may participate directly in the replicase complex. Of these proteins, Hsp90 is a chaperone protein and cyclophilin A is a co-chaperone protein.…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 72 Is Associated with the Hepatitis C Virus Replicase Complex and Enhances Viral RNA Replication

Chen¹,

Chen²,

Chow

et al. 2010

Journal of Biological Chemistry

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The NS5A protein of the hepatitis C virus (HCV) is an integral component of the viral replicase. It also modulates cellular signaling and perturbs host interferon responses. The multifunctional characteristics of NS5A are mostly attributed to its ability to interact with various cellular proteins. This study aimed to identify the novel cellular factors that interact with NS5A and decipher the significance of this interaction in viral replication. The NS5A-interacting proteins were purified by the tandem affinity purification (TAP) procedure from cells expressing NS5A and identified by mass spectrometry. The chaperone protein Hsp72 was identified herein. In vivo protein-protein interaction was verified by co-immunoprecipitation and an in situ proximity ligation assay. In addition to NS5A, Hsp72 was also associated with other members of the replicase complex, NS3 and NS5B, suggesting that it might be directly involved in the HCV replication complex. Hsp72 plays a positive regulatory role in HCV RNA replication by increasing levels of the replicase complex, which was attributed either to the increased stability of the viral proteins in the replicase complex or to the enhanced translational activity of the internal ribosome entry site of HCV. The fact that the host chaperone protein Hsp72 is involved in HCV RNA replication may represent a therapeutic target for controlling virus production. The hepatitis C virus (HCV),3 a hepacivirus in the Flaviviridae family, is the leading cause of acute and chronic hepatitis worldwide (1, 2). Currently, around 170 million individuals are chronically infected with HCV. HCV infection often leads to liver cirrhosis and hepatocellular carcinoma (1-3).The replication of HCV is entirely cytoplasmic. The HCV lifecycle starts when enveloped virus particles attach to the cell membrane and interact with specific surface receptor(s). After internalization and membrane fusion in an endosome, the HCV genome is released into the cytoplasm. This genome serves not only as the messenger RNA for the translation of viral proteins but also as the template for viral RNA replication. All viral proteins are directly or indirectly associated with the endoplasmic reticulum (ER) membrane, where replication and assembly take place. The HCV non-structural proteins, NS3/NS4A, NS4B, NS5A, and NS5B, and likely several host-derived factors function as a replicase complex, which executes the replication process. Once the newly synthesized nascent RNA is packaged in the particle, the virion forms by budding into the ER and leaves the cell through the secretory pathway (4 -7).Among the HCV viral proteins, NS5A has been demonstrated to be multi-functional, which supports the replication and survival of HCV. The requirement for NS5A in HCV RNA replication has been supported by numerous lines of evidence (8 -17). The other important functions of NS5A lie in its potential to perturb the interferon responses and modulate the signaling pathways of host cells; those are mostly dependent on its interaction with cellular ...

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Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7‐Tetrahydrobenzo[1,2‐d]thiazole Derivatives

et al. 2019

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Cellular chaperones that belong to the heat‐shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5,6,7‐tetrahydrobenzo[1,2‐d]thiazole‐2‐amine structure show inhibition of HCV replication and binding to Hsp90, a series of twelve novel compounds based on this scaffold was designed and synthesized. The aim was improved Hsp90 affinity and anti‐HCV activity. Through structural optimization, improved binding to Hsp90 and specific HCV inhibition in genotype 1b and 2a replicon models was achieved for three compounds belonging to the newly synthesized series. Furthermore, these compounds efficiently inhibited replication of full‐length HCV genotype 2a in a reporter virus RNA assay with IC50 values ranging from 0.03 to 0.6 μm.

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Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90

Cited by 225 publications

References 53 publications

Hepatitis C Virus NS5A Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Contributing to Cell Survival by Disrupting the Interaction between FK506-binding Protein 38 (FKBP38) and mTOR

Hepatitis C Virus NS5A Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Contributing to Cell Survival by Disrupting the Interaction between FK506-binding Protein 38 (FKBP38) and mTOR

Heat Shock Protein 72 Is Associated with the Hepatitis C Virus Replicase Complex and Enhances Viral RNA Replication

Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7‐Tetrahydrobenzo[1,2‐d]thiazole Derivatives

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