Proteasomes regulate hepatitis B virus replication by degradation of viral core-related proteins in a two-step manner.
The cellular proteasomes presumably inhibit the replication of hepatitis B virus (HBV) due to degradation of the viral core protein (HBcAg). Common proteasome inhibitors, however, either enhance or inhibit HBV replication. In this study, the exact degradation process of HBcAg and its influences on HBV replication were further studied using bioinformatic analysis, protease digestion assays of recombinant HBcAg, and proteasome inhibitor treatments of HBV-producing cell line HepG2.2.15. Besides HBcAg and hepatitis B e antigen precursor, common hepatitis B core-related antigens (HBcrAgs), the small and the large degradation intermediates of these HBcrAgs (HBcrDIs), were regularly found in cytosol of HepG2.2.15 cells. Further, the results of investigation reveal that the degradation process of cytosolic HBcrAgs in proteasomes consists of two steps: the limited proteolysis into HBcrDIs by the trypsin-like (TL) activity and the complete degradation of HBcrDIs by the chymotrypsin-like (chTL) activity. Concordantly, HBcrAgs and the large HBcrDI or HBcrDIs (including the small HBcrDI) were accumulated when the TL or chTL activity was inhibited, which generally correlated with enhancement and inhibition of HBV replication, respectively. The small HBcrDI inhibited HBV replication by assembling into the nucleocapsids and preventing the victim particles from being mature enough for envelopment. The two-step degradation manner may highlight some new anti-HBV strategies.
Hepatology Laboratory, The Hospital for Liver Disease, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.|Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.|Jinan University Clinic, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, China.
Zi-Hua
ZH
Zheng
Hepatology Laboratory, The Hospital for Liver Disease, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.|Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
Hui-Ying
HY
Yang
Liver Disease Key Laboratory of Guangdong Province, Guangzhou, 510630, Guangdong, China.
Lin
L
Gu
Hepatology Laboratory, The Hospital for Liver Disease, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China. xiaomoupeng2016@sina.com.|Liver Disease Key Laboratory of Guangdong Province, Guangzhou, 510630, Guangdong, China. xiaomoupeng2016@sina.com.
Xiao-Mou
XM
Peng
D045744:Cell Line, Tumor; D004261:DNA Replication / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000821:virology; D006512:Hepatitis B Core Antigens / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000821:virology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D059748:Proteolysis; D014758:Viral Core Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*
D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D014758:Viral Core Proteins; D046988:Proteasome Endopeptidase Complex
HBcrAgs; Hepatitis B virus; Proteasomes; Protein degradation; Viral replication