Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation

Liu, Bo; Fang, Man; Hu, Ye; Huang, Baoshan; Li, Ning; Chang, Chunmei; Huang, Rui; Xu, Xinlin; Zhou, Yang; Chen, Zhi; Liu, Wei

doi:10.4161/auto.27286

Cited by 141 publications

(150 citation statements)

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“…However, how autophagy might implement regulation and help pathogen escape from the following autophagic degradation still remained elusive. A recent study demonstrated that hepatitis B virus x protein impaired lysosomal degradative capacity by disturbing its acidification without influencing the fusion of autophagosomes and lysosomes (27). Intriguingly, one of the most important findings from our current study turned out that the fusion of autophagosomes and lysosomes was hampered in pHepG2 cells.…”

Section: Discussionsupporting

confidence: 49%

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

Zhou

Jin

Ding

et al. 2016

BST

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Section: Discussionsupporting

confidence: 49%

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

Zhou

Jin

Ding

et al. 2016

BST

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“…Evidence indicates that HBV can activate autophagosome formation, which is required for its own replication (28)(29)(30)(31)(32). Furthermore, HBx appears to play an important role in HBV-induced autophagosome formation (28,(33)(34)(35)(36). HBx may contribute to the induction of autophagy in hepatocytes by enhancing the activity of VPS34 (28) or by upregulating beclin-1 expression (33,34).…”

mentioning

confidence: 99%

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Zhong

Shu

Dai

et al. 2017

J Virol

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Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.KEYWORDS HBV X protein, autophagy, signaling pathway, viral replication H epatitis B virus (HBV) is an important human pathogen that can cause a wide spectrum of liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). The HBV genome is about 3.2 kb in length, carrying four genes named

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“…17,30 For instance, lysosome damage induced by aminochrome resulted in autophagy disorder, 31 and HBV X protein could inhibit autophagic degradation through destroying the nature of lysosomes. 32 The current investigations on SiNPs and autophagy are mostly focused on autophagy detection; however, the mechanisms of autophagosome accumulation and whether the autophagic flux was blocked remain unclear. Therefore, further detailed investigation of the effects of SiNPs on autophagy and the specific molecular mechanisms are urgently needed.…”

mentioning

confidence: 99%

Silica nanoparticles induce autophagy dysfunction via lysosomal impairment and inhibition of autophagosome degradation in hepatocytes

Wang

Lu³

et al. 2017

IJN

162

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Autophagy dysfunction is considered as a potential toxic mechanism of nanomaterials. Silica nanoparticles (SiNPs) can induce autophagy, but the specific mechanism involved remains unclear. Therefore, the aim of this study was to confirm the effects of SiNPs on autophagy dysfunction and explore the possible underlying mechanism. In this article, we reported that cell-internalized SiNPs exhibited dose- and time-dependent cytotoxicity in both L-02 and HepG2 cells. Multiple methods verified that SiNPs induced autophagy even at the noncytotoxic level and blocked the autophagic flux at the high-dose level. Notably, SiNPs impaired the lysosomal function through damaging lysosomal ultrastructures, increasing membrane permeability, and downregulating the expression of lysosomal proteases, cathepsin B, as evidenced by transmission electron microscopy, acridine orange staining, quantitative reverse transcription-polymerase chain reaction, and Western blot assays. Collectively, these data concluded that SiNPs inhibited autophagosome degradation via lysosomal impairment in hepatocytes, resulting in autophagy dysfunction. The current study not only discloses a potential mechanism of autophagy dysfunction induced by SiNPs but also provides novel evidence for the study of toxic effect and safety evaluation of SiNPs.

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Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation

Cited by 141 publications

References 50 publications

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

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

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Silica nanoparticles induce autophagy dysfunction via lysosomal impairment and inhibition of autophagosome degradation in hepatocytes

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Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation

Cited by 141 publications

References 50 publications

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

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

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Silica nanoparticles induce autophagy dysfunction via lysosomal impairment and inhibition of autophagosome degradation in hepatocytes

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Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction