O ‐GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels

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Abstract
O ‐GlcNAcylation is a form of posttranslational modification, and serves various functions, including modulation of location, stability, and activity for the modified proteins. O ‐linked‐ N ‐acetylglucosamine ( O ‐GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies the cellular proteins with O ‐GlcNAc moiety. Early studies reported that the decreased O ‐GlcNAcylation regulates cellular autophagy, a process relevant for hepatitis B virus replication (HBV) and assembly. Therefore, we addressed the question how O ‐GlcNAcylation regulates cellular autophagy and HBV replication. Inhibition of OGT activity with a small molecule inhibitor OSMI‐1 or silencing OGT significantly enhanced HBV replication and HBsAg production in hepatoma cells and primary human hepatocytes (PHHs). Western blotting analysis showed that inhibition of O ‐GlcNAcylation‐induced endoplasmic reticulum (ER) stress and cellular autophagy, two processes subsequently leading to enhanced HBV replication. Importantly, the numbers of autophagosomes and the levels of autophagic markers LC3‐II and SQSTM1/p62 in hepatoma cells were elevated after inhibition of O ‐GlcNAcylation. Further analysis revealed that inhibition of O ‐GlcNAcylation blocked autophagosome‐lysosome fusion and thereby prevented autophagic degradation of HBV virions and proteins. Moreover, OSMI‐1 further promoted HBV replication by inducing autophagosome formation via inhibiting the O ‐GlcNAcylation of Akt and mTOR. In conclusion, decreased O ‐GlcNAcylation enhanced HBV replication through increasing autophagosome formation at multiple levels, including triggering ER‐stress, Akt/mTOR inhibition, and blockade of autophagosome‐lysosome fusion.
Funding Information
  • Deutsche Forschungsgemeinschaft (TRR60)
  • Universität Duisburg-Essen

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