atp gamma s Recently some published studies showed
Recently, some published studies showed that HBV can induce autophagy in vitro and vivo [, , ]. The critical role of autophagy in HBV normal life cycle, such as HBV envelopment, has been gradually accepted by researchers from different laboratories [22,23]. HBV can trigger the autophagic pathway, through which viruses can be activated to promote their DNA replication [22,23]. According to recent publications, in chronic HBV hepatitis, early stage of autophagy could benefit HBV replication, thus worsening the condition of liver infection [24,25]. Moreover, it has been shown that HCC has a close relationship with HBV-induced autophagy. When the diseases worsen to HCC, activated autophagy could attenuate tumor progression through autophagic cell death and anti-tumor immune response [, , , ]. Thus, these reports indicate that autophagy may be an important and novel target for HBV infection and its related diseases. In this review, we will discuss and summarize some main findings.
HBV structure HBV is a hepadnavirus DNA virus. It comprises a protein, lipid envelope and an icosahedral nucleocapsid core containing a partially double-stranded circular DNA (relaxed circular DNA or rcDNA) [, , , ].When HBV infects hepatocytes, HBV genome-containing capsid is internalized in cytoplasm, and releases rcDNA into nucleus. Then the rcDNA is repaired by host enzymes and converted to covalently closed circular DNA (cccDNA), which consists nucleosome-bound minichromosome, serving as a template of viral messenger RNAs (mRNAs) production [31,32]. HBV genome encodes four overlapping open reading frames S, X, C, P regions. These genes are translated into essential viral proteins including HBV small/medium/large(S/M/L) surface proteins(HBs), HBV X proteins (HBx), HBV core antigen (HBcAg) and polymerase [28,31].HBs consist the envelope and act as atp gamma s . HBcAg can be found in nucleocapsid core and serves as a marker of viral replication . HBx is required for HBV replication and evidences showed that HBx promotes HCC progression for it promoting pro-carcinogenic genes expression, inhibiting tumor suppressor protein function and prolonging hepatocytes life cycle [33,34].
HBV induces autophagic response In current studies, the researchers demonstrated that HBV can induce autophagic response. They transfected pHBV1.3 into HepG2 cells and Huh7 cells, then observed that LC3-II/LC3-I and accumulation of autophagic vacuoles can be enhanced in comparison with control group [2,23]. Wang et al. also confirmed the up-regulated LC3-II/LC3-I in HepG2.2.15 which is a version of HepG2 transfected with HBV DNA that expresses HBV constitutively . Some articles reported that HBV enhances autophagic flux (early autophagy stage) and exerts minimal effect on rates of autophagic protein degradation. Sir D et al. first proposed the idea that HBV can activate the early autophagic pathway . Li et al. then indicated that the endoplasmic reticulum (ER) stress triggered by S proteins can initiate unfolded protein response (UPR), which sufficiently induces autophagosome formation  (Fig. 1). These days, the role of HBx in HBV-induced early autophagy stage is also well-received  (Fig. 1). HBx-induced activation of classes I and III phosphoinositide 3-kinase signaling (PI3K) pathways, mitogen-activated protein kinase (MAPK) pathway, reactive oxygen species (ROS)/c-Jun N-terminal kinases (JNK) signaling pathway and Adenosine monophosphate-activated protein kinase (AMPK) are all involved in autophagosome formation [20,, , ]. However, Liu et al. believed that HBV also hampers autophagy maturation. They confirmed that HBx protein impaired lysosomal degradative capacity by disturbing its acidification without influencing fusion of autophagosomes and lysosomes [40,41]. During the lifetime of HBV, autophagy may involve viral DNA replication, envelopment of viral particles and promote their release from cellular membranes [22,23]. In short, HBV-induced autophagy accelerates HBV production.