Proteasomal processing of the viral replicase ORF1 facilitates HEV-induced liver fibrosis
Abstract
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 H EV- D erived S MAD A 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Fei Zhang
Ling-Dong Xu
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine
Shiying Wu
Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University
Qirou Wu
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine
Ailian Wang
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine
Shengduo Liu
Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University
Qian Zhang
Xinyuan Yu
Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University
Bin Wang
Yinghao Pan
Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University
Fei Huang
Dante Neculai
Department of Cell Biology Zhejiang University School of Medicine
Bing Xia
Xin-Hua Feng
Ministry of Education Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University
Li Shen
Qi Zhang
Tingbo Liang
Yao-Wei Huang
State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University
Pinglong Xu
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine