Proteasomal processing of the viral replicase ORF1 facilitates HEV-induced liver fibrosis
Chronic infections with hepatitis E virus (HEV), especially those of genotype 3 (G3), frequently lead to liver fibrosis and cirrhosis in patients. However, the causation and mechanism of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we found that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin-proteasomal processing leading to formation of the <u>H</u>EV-<u>D</u>erived <u>S</u>MAD <u>A</u>ctivator (HDSA), a viral polypeptide lacking putative helicase and RNA polymerase domains. The HDSA is stable, non-HSP90-bound, localizes to the nucleus, and is abundant in G3 HEV-infected hepatocytes of various origins. Markedly, the HDSA in hepatocytes potentiates the fibrogenic TGF-β/SMAD pathway by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, leading to significant fibrosis in HEV-susceptible gerbils. Virus infection-induced liver fibrosis in HEV-susceptible gerbils could be prevented by mutating the residues P989C, A990C, and A991C (PAA-3C) within ORF1, which are required for proteasomal processing. Thus, we have identified a viral protein derived from host proteasomal processing, defined its notable role in liver fibrosis and highlighted the nature of an unanticipated host-HEV interaction that facilitates hepatitis E pathogenesis.
Authors
- Tingbo Liang (ORCID: https://orcid.org/0000-0003-3262-2587)
- Yao‐Wei Huang (ORCID: https://orcid.org/0000-0001-9755-8411)
- Qirou Wu (ORCID: https://orcid.org/0009-0001-5659-2186)
- Pinglong Xu (ORCID: https://orcid.org/0000-0001-7726-5443)
- Shengduo Liu
- Bing Xia (ORCID: https://orcid.org/0000-0002-1637-7908)
- Xin‐Hua Feng (ORCID: https://orcid.org/0000-0002-4418-0811)
- Fei Huang (ORCID: https://orcid.org/0000-0003-3263-0675)
- Xinyuan Yu (ORCID: https://orcid.org/0000-0002-9746-9416)
- Dante Neculai (ORCID: https://orcid.org/0000-0001-8887-9168)
- Qi Zhang (ORCID: https://orcid.org/0000-0001-7959-817X)
- Bin Wang (ORCID: https://orcid.org/0000-0002-2585-3160)
- Qian Zhang (ORCID: https://orcid.org/0000-0001-9924-6024)
- Fei Zhang (ORCID: https://orcid.org/0000-0002-9179-6539)
- Li Shen (ORCID: https://orcid.org/0000-0002-5696-2191)
- Shiying Wu (ORCID: https://orcid.org/0009-0000-8108-6341)
- Yinghao Pan (ORCID: https://orcid.org/0009-0004-7686-884X)
- Ling-Dong Xu
- Ailian Wang
Institutions
- South China Agricultural University (CN)
- Westlake University (CN)
- Zhejiang Cancer Hospital (CN)
- Zhejiang Lab (CN)
- Hangzhou Cancer Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang Gongshang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1073/pnas.2419946122
- Citations
- 7
- Primary Topic
- Hepatitis Viruses Studies and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 9.25
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China