br S proteins and HBV induced autophagy HBV surface proteins
S proteins and HBV-induced autophagy HBV surface proteins (S proteins or HBs) are reported to trigger HBV-induced autophagy by inducing ER stress and UPR in host Axitinib .
HBx and HBV-induced autophagy HBx is a multifunctional viral protein. It can regulate virus replication, promote cell life cycle progression, induction of cell growth arrest and modulation of proteolytic degradation pathways in cells [35,55]. Present studies indicated that HBx can increase autophagosomes and autolysosomes formation. The authors found that BECN1, PI3KC3, Sirt1, ROS/JNK and AMPK were upregulated after HBx stimulated [20,23,, , ] (Fig. 1). All these activated proteins as well as their downstream counts for the HBV-induced autophagy. One should note that a group has reported findings that HBx triggers autophagy in HepG2 and HepG2.2.15 . Indeed, the data showed HBx increases the mTOR expression, however mTOR may play a negative role in HBx-induced autophagy, for the addition of mTOR inhibitor rapamycin enhanced HBx-induced autophagy . Some agents including AMPK induce autophagy by down regulating mTOR . Moreover, HBx has been shown to impair V-ATPase in lysosomes, there for impedes the maturation of autophagosome . In summary, the HBx play role in early and late stage of autophagy.
Autophagy and HBV replication The knowledge that autophagy is correlated with HBV replication is accepted these days  (Fig. 1). Several laboratories have demonstrated that autophagy suppression will inhibit HBV replication; this finding indicates the positive role of autophagy in the life of HBV [22,23,, , ]. These studies included detection of HBV-infected cells, cells transfected by HBV genomic DNA, or stable cells exhibiting HBV DNA replication. Sir et al. reported that autophagy induction by HBV requires HBx, which binds to PI3KC3 to enhance its activity; most of the effects of HBx on HBV DNA replication in HepG2 cells may be mediated by PI3KC3 and autophagy [23,70]. By using 3-methyladenine (3-MA) (a specific PI3KC3 inhibitor) or suppressing Vps34 expression (the catalytic subunit of PI3KC3 and interfered by siRNA), researchers demonstrated that in resemblance to nutrient starvation, PI3KC3 plays a critical role in HBV-induced autophagy. Suppression of PI3KC3 activity or inhibition of expression of Atg7, which is an enzyme essential for autophagosome formation, result in reduction of HBV replication . The authors claimed that autophagy suppression slightly reduces HBV RNA levels and pgRNA packaging but suppressed HBV DNA replication significantly. . This phenomenon indicates that autophagy enhances HBV replication mostly at the viral DNA replication step . Subsequent to the report of Sir et al., another group of scientists also reported that HBV-induced autophagy positively affected HBV replication in cell cultures but primarily at the step of envelopment (13). To determine whether autophagy machinery performs an antiviral or proviral function during HBV infection, the authors tested the effects of autophagy inhibitor 3-MA and siRNA duplex-mediated knockdown of key autophagy proteins on viral replication in Huh7 cells. They discovered that these disposals significantly diminished the level of extracellular virions but showed only a slight inhibitory effect on the level of nucleocapsid-associated DNA . The findings above are refutable as the use of different HBV strains or different sublines of Huh7 cells in their studies may account for these ambiguities; their interpretations also remain unelucidated. Moreover, some studies suggested that HBV-induced ROS facilitates HBV replication and capsid assembly in host cells [72,73]. Current data do support the view that HBV-induced autophagy facilitate viral replication via ROS/JNK signaling . Further, Döring et al. confirmed that HBV could promote itself replication and maturation by subverting Atg5/Atg12/Atg16L to be the component of prime autophagic without Atg8/LC3 lipidation . In the meanwhile, some publications hold the opposite view that HBV-induced autophagy suppress HBV replication. Wu et al. indicated that autophagy induced by HBV could degradate envelope proteins . Lazar et al. confirmed that the degradation of HBV envelope proteins is mediated by ER degradation-enhancing, mannosidase-like proteins (EDEM) which are upregulated to relieve UPR [75,76]. Furthermore, Xie et al. confirmed that HBV replication could be restricted by PRKAA/AMPK-enhanced autophagic degradation . The exact relation between autophagy and HBV replication requires further research.