Hepatitis E virus ORF1 processing linked to liver fibrosis

What is it about?

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. HEV is a positive-strand RNA virus, and its ORF1 encodes a putative multi-domain replicase protein. This study 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.

Featured Image

Why is it important?

How sustained HEV infection can trigger the frequent occurrence of liver fibrosis is less understood. On the other hand, viral proteases typically cleave the replicase polyprotein into mature proteins in positive-strand RNA viruses. However, since the putative papain-like cysteine protease 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. The study reported the identification of an unexpectedly novel protein in HEV for the first time and conducted systematic studies on its production, function, and pathogenic mechanism associated with liver fibrosis.

Perspectives