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Hepatitis B virus production is modulated through microRNA-99 family induced-autophagy

Lin, Yong

MiRNAs are highly conserved small noncoding RNAs which are widely expressed in multicellular organisms and participate in the regulation of various cellular processes, including autophagy and viral replication. Evidently, miRNAs are able to modulate host gene expression and thereby inhibit or enhance HBV replication. Interestingly, the plasma levels of miR-99 family in the peripheral blood correspond with HBV DNA loads. As previous studies identified, the mRNA of IGF-1R, Akt, and mTOR as direct targets with binding sites for miR-99 family members. Thus, we addressed whether the miR-99 family regulated HBV replication and analyzed the underlying molecular mechanism. We found that ectopic expression of miR-99 family members could markedly increase HBV replication, progeny secretion, and antigen expression in hepatoma cells. However, miR-99 family members showed no effect on modulating HBV transcription and HBV promoter activities, suggesting that they may regulate HBV replication through other mechanisms. Consistent with bioinformatic analysis and recent reports, we further found that ectopic expression of miR-99 family attenuated IGF-1R/Akt/mTOR signaling pathway and repressed insulin-stimulated activation in hepatoma cells. Moreover, the experimental data revealed that the miR-99 family promoted the formation of autophagosomes through inhibiting the phosphorylation of ULK1, followed with the autophagic degradation of cargo receptor SQSTM1/p62. Thus, these results implied that the miR-99 family enhanced HBV replication through mTOR/ULK1 signaling induced complete autophagy. We further explored the definite mechanisms of different autophagic phases affecting HBV production. Consistent with our findings by silencing the components of ULK1 complex or using autophagic inhibitor 3-MA, HBV replication and HBsAg production were significantly decreased by silencing of Rab5. In contrast, silencing of Rab7 significantly enhanced HBV replication and HBsAg production, while activation of Rab7 obviously decreased the levels of HBV production. Thus, these data indicated that the delivery of HBV capsids and HBsAg to lysosomes could facilitate their degradation. Conclusion: the miR-99 family promotes HBV replication post-transcriptionally through IGF-1R/PI3K/Akt/mTOR/ULK1 signaling-induced complete autophagy. We provide new evidence that HBV replication and HBsAg production requires early autophagic process, but may be degraded to a significant extent in the autophagosome compartment.

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Lin, Yong: Hepatitis B virus production is modulated through microRNA-99 family induced-autophagy. 2017.

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