HBV secretion is regulated through the activation of endocytic and autophagic compartments via Rab7 stimulation

Abstract

The cellular mechanisms by which hepatitis B virus (HBV) is assembled and exported are largely undefined. Recently, it has been suggested that these steps require the multivesicular body (MVB) and the autophagic machinery. However, the mechanisms by which HBV might regulate these compartments are unclear. In this study, we have found that by activating Rab7a, HBV alters its own secretion by inducing dramatic changes in the morphology of MVB and autophagic compartments. These changes are characterized by the formation of numerous tubules that are dependent upon the increase in Rab7 activity observed in the HBV-expressing HepG2.2.15 cells compared to HepG2 cells. Interestingly, transfection-based expression of the five individual viral proteins indicated that the precore protein, which is a precursor of HBeAg, was largely responsible for the increased Rab7 activity. Finally, small interfering RNA (siRNA)-mediated depletion of Rab7 significantly increased the secretion of virions, suggesting that reduced delivery of the virus to the lysosome facilitates viral secretion. These findings provide novel evidence indicating that HBV can regulate its own secretion through an activation of the endo-lysosomal and autophagic pathway mediated by Rab7 activation.

Hepatitis B virus dampens autophagy maturation via negative regulation of Rab7 expression

“…Hampered fusion of autophagsomes and lysosomes caused by deficiency of Rab7 has also been covered in human parainfluenza virus infection (11). Moreover, Inoue J et al has reported that HBV could hijack Rab7 for its replication, as siRNA-mediated depletion of Rab7 dramatically augmented the secretion of virions (31). Accordingly, our data showed that HBV infection inhibited Rab7 expression in pHepG2 cells and HepG2.2.15 cells.…”

Prediction of HBF-0259 interactions with hepatitis B Virus receptors and surface antigen secretory factors

“…The HBF-0259 mechanism of effect on HBsAg secretion inhibition is still unknown [4,42]. For this, we performed docking on known cellular factors involved in HBsAg and HBV particle secretion including CypA, Annexin II and Rab7 [10,13,26]. Our results showed that the interaction energy of HBF-0259 to CypA (-545.41 kcal/mol) was obviously higher than Annexin II and Rab7 (Table 3).…”

“…The interaction energy of HBF-0259 to PreS1 and PreS2 [1][2][3][4][5][6][7][8][9][10][11] were lower comparing to other predicted receptors. HBF-0259 obviously interacts more strongly with SCCA1.…”

“…Amino acids involved in interaction site of HBF-0259 were analyzed for conservancies among target molecules including, SCCA1, FNIII 1 , preS2 [1][2][3][4][5][6][7][8][9][10][11] , NTCP 84-165 , FTL, ASGPRCRD, preS1 . The results showed no conserved sequences in any of mentioned receptors ( Table 2).…”

“…In this study, in order to predict the mechanism(s) of action by which HBF-0259 decreases HBsAg secretion, we predict the interaction of HBF-0259 with suggested HBV receptors, preS regions of HBsAg (preS1 and preS2 [1][2][3][4][5][6][7][8][9][10][11] ) and cellular HBsAg secreting factors by computational approaches (Table 1).…”