Hepatitis E virus (HEV) is one of the leading causes of viral hepatitis in humans, with roughly 20 million infections every year and approximately 60,000 HEV-related deaths. Sporadic and cluster cases of hepatitis E disease in industrialized societies are caused mainly by the spread and sustained infection of zoonotic genotype 3 (G3) or G4 HEV upon food-borne transmission. Immunocompromised individuals, including patients with HIV, organ transplant recipients, and those receiving chemotherapy or with rheumatic disorders, are prone to chronic infection by G3 HEV. One-tenth of patients with chronic HEV infection undergo rapid progression of liver fibrosis to cirrhosis, leading to deadly cirrhosis within 2–3 years. Nevertheless, how sustained HEV infection can trigger the frequent occurrence of liver fibrosis is less understood. HEV is a positive-strand RNA virus, and its ORF1 encodes a putative multi-domain replicase protein comprising methyltransferase (Met), Y domain (Y), a presumed papain-like cysteine protease (PCP), hypervariable region (HVR), Macro domain (or X domain), helicase (Hel), and RNA-dependent RNA polymerase (RdRp). Viral proteases typically cleave the replicase polyprotein into mature proteins in positive-strand RNA viruses. However, since the putative PCP in HEV ORF1 lacks protease activity, whether and how the full-length ORF1 polyprotein is processed to function during HEV infection is a long-standing question.
A research team, co-led by Dr. Pinglong Xu from Zhejiang University and Dr. Yao-Wei Huang from the State Key Laboratory for Animal Disease Control and Prevention at South China Agricultural University, has been dedicated to tackling this challenge over the past several years. They found that HEV ORF1 undergoes unique ubiquitin-proteasomal processing to generate a novel viral protein, HEV-Derived SMAD Activator (HDSA). HDSA is the first known viral protein the proteasomal system produces, lacking helicase and RdRp domains. It is stable, non-HSP90-bound, nuclear localization, and comparatively abundant in G3 HEV-infected hepatocytes of various origins. Markedly, HDSA significantly potentiates the fibrogenic TGF-β/SMAD pathway in hepatocytes by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, thus leading to significant fibrosis in HEV-susceptible gerbils. Fibrosis in HEV-susceptible livers could be prevented by mutating the proteasomal processing site on viral HDSA or by pharmacological blockade of TGF-β/SMAD signaling.
Therefore, this cross-disciplinary study identified the first viral protein (HDSA) derived from the host proteasomal processing and offers a new mechanism for processing positive-sense RNA virus polyproteins independent of viral protease activity. It sheds light on the underlying mechanisms for liver fibrosis by sustained HEV infection and highlights the intricate nature of an unanticipated host-HEV interaction that facilitates hepatitis E pathogenesis.
Read the full research article (Proc Natl Acad Sci U S A. 2025 March 12; 122(11): e2419946122): DOI: 10.1073/pnas.2419946122
