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Inhibition of Cellular Factor TM6SF2 Suppresses Secretion Pathways of Hepatitis B, Hepatitis C, and Hepatitis D
Thomas Tu1,2, Harout Ajoyan1, Rifqiyah Nur Umami1,3
1Storr Liver Centre, The Westmead Institute for Medical Research.
Insights
Transmembrane 6 superfamily member 2 (TM6SF2) protein is crucial for the secretion of hepatitis B, C, and D viruses. Targeting TM6SF2 may lead to new pan-viral therapies for chronic viral hepatitis.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Chronic viral hepatitis, caused by HBV, HCV, and HDV, relies on host cell machinery for viral particle secretion.
- The endoplasmic reticulum-Golgi pathway is essential for the secretion of these viruses, presenting a potential therapeutic target.
Purpose of the Study:
- To investigate the role of the host protein transmembrane 6 superfamily member 2 (TM6SF2) in the secretion of HBV, HCV, and HDV.
- To explore TM6SF2 as a potential target for novel pan-viral therapeutic agents.
Main Methods:
- Utilized virus cell culture models to assess the impact of TM6SF2 knockdown on viral secretion.
- Analyzed a cohort of patients with hepatitis B to correlate a specific TM6SF2 polymorphism (rs58542926 CT/TT) with viral particle concentrations in blood.
Main Results:
- Knockdown of TM6SF2 in cell culture models significantly reduced the secretion of infectious HCV, HDV, and HBV subviral particles.
- A TM6SF2 polymorphism associated with reduced liver TM6SF2 levels correlated with lower concentrations of HBV subviral particles in patients.
- These findings complement previous research demonstrating decreased HCV viral load in individuals with this polymorphism.
Conclusions:
- The host protein TM6SF2 is essential for the secretion of HBV, HCV, and HDV.
- TM6SF2 represents a promising target for the development of new pan-viral therapeutic strategies against chronic viral hepatitis.
Abstract:
Chronic viral hepatitis is caused by hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). Despite different replication strategies, all of these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions, and HBV subviral particles. Moreover, in a cohort of people with hepatitis B, a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV, and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis.
