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Celastrol attenuates hepatitis C virus translation and inflammatory response in mice by suppressing heat shock protein 90β

Acta Pharmacologica Sinica volume 44, pages 1637–1648 (2023)Cite this article

Abstract

Hepatitis C virus (HCV) infection is one of the major factors to trigger a sustained hepatic inflammatory response and hence hepatocellular carcinoma (HCC), but direct-acting-antiviral (DAAs) was not efficient to suppress HCC development. Heat shock protein 90 kDa (HSP90) is highly abundant in different types of cancers, and especially controls protein translation, endoplasmic reticulum stress, and viral replication. In this study we investigated the correlation between the expression levels of HSP90 isoforms and inflammatory response marker NLRP3 in different types of HCC patients as well as the effect of a natural product celastrol in suppression of HCV translation and associated inflammatory response in vivo. We identified that the expression level of HSP90β isoform was correlated with that of NLRP3 in the liver tissues of HCV positive HCC patients (R2 = 0.3867, P < 0.0101), but not in hepatitis B virus-associated HCC or cirrhosis patients. We demonstrated that celastrol (3, 10, 30 μM) dose-dependently suppressed the ATPase activity of both HSP90α and HSP90β, while its anti-HCV activity was dependent on the Ala47 residue in the ATPase pocket of HSP90β. Celastrol (200 nM) halted HCV internal ribosomal entry site (IRES)-mediated translation at the initial step by disrupting the association between HSP90β and 4EBP1. The inhibitory activity of celastrol on HCV RNA-dependent RNA polymerase (RdRp)-triggered inflammatory response also depended on the Ala47 residue of HSP90β. Intravenous injection of adenovirus expressing HCV NS5B (pAde-NS5B) in mice induced severe hepatic inflammatory response characterized by significantly increased infiltration of immune cells and hepatic expression level of Nlrp3, which was dose-dependently ameliorated by pretreatment with celastrol (0.2, 0.5 mg/kg, i.p.). This study reveals a fundamental role of HSP90β in governing HCV IRES-mediated translation as well as hepatic inflammation, and celastrol as a novel inhibitor of HCV translation and associated inflammation by specifically targeting HSP90β, which could be developed as a lead for the treatment of HSP90β positive HCV-associated HCC.

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Fig. 1: Correlation of the expression levels of NLRP3, HSP90α, and HSP90β in patients’ samples.
Fig. 2: Celastrol interacted with Hsp90β by binding to the NBD ATPase pocket.
Fig. 3: Celastrol exhibited a potent inhibitory effect against HCV in Huh-luc/neo-ET genotype 1b replicon cells.
Fig. 4: The anti-HCV activity of celastrol is dependent on the ATPase activity of HSP90β but not HSP90α.
Fig. 5: Treatment with celastrol inhibited the translation of HCV.
Fig. 6: Role of HSP90β in celastrol-inhibited IRES-dependent translation in HCV genotype 1b cells.
Fig. 7: Celastrol suppressed HCV NS5B induced inflammatory response in vivo depending on HSP90β.

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Acknowledgements

The authors thank Mr. Rui-feng Li and Dr. Zi-feng Yang from The First Affiliated Hospital of Guangzhou Medical University for anti-influenza activity, Dr. Martin Holcik from the University of Ottawa, Dr. Tyson Graber from McGill University, and Dr. Yan-dong Zhang from South University of Science and Technology of China for discussion of polysome profiling. This work was partially supported by Macao Science and Technology Development Fund (grant number 0092/2021/A2), Research Fund of the University of Macau (grant number MYRG 2019-00015-ICMS), and Shenzhen-Hong Kong-Macao Science and Technology Innovation Project (Category C) (grant number SGDX2020110309260100). The authors also appreciate the support from Animal Research Core at the University of Macau.

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Authors and Affiliations

  1. Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao SAR, China

    Shao-ru Chen, Zheng-qing Li, Mo-yu Ding & Ying Wang

  2. Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China

    Jun Xu

  3. National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, China

    Ya-ming Shan

  4. Department of Pharmacology, Yale University, New Haven, CT, 06510, USA

    Yung-chi Cheng

  5. Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou, 510632, China

    Gao-xiao Zhang, Ye-wei Sun & Yu-qiang Wang

  6. Guangzhou Magpie Pharmaceuticals Co., Ltd., Guangzhou International Business Incubator, Guangzhou, 510663, China

    Yu-qiang Wang

  7. Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, China

    Ying Wang

  8. Minister of Education Science Center for Precision Oncology, University of Macau, Macao SAR, China

    Ying Wang

  9. Minister of Education Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China

    Ying Wang

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Contributions

SRC and ZQL conducted the major experiments. JX, MYD, YMS, YWS, and GXZ took part and assisted in some experiments. YCC performed part of the data analysis. YQW and YW designed the experiments and performed data analysis. YW summarized all the results and gave indispensable guidance to the entire study, wrote and revised the manuscript. All authors read and approved the submitted manuscript.

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Correspondence to Ying Wang.

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Chen, Sr., Li, Zq., Xu, J. et al. Celastrol attenuates hepatitis C virus translation and inflammatory response in mice by suppressing heat shock protein 90β. Acta Pharmacol Sin 44, 1637–1648 (2023). https://doi.org/10.1038/s41401-023-01067-w

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