Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes

Shrivastava, Shubham; Raychoudhuri, Amit; Steele, Robert; Ray, Ranjit

doi:10.1002/hep.24073

Cited by 180 publications

(185 citation statements)

References 40 publications

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“…It seems to be dependent on the virus, on the phases of its life cycle, and on host cell type. Regarding the relationship between autophagy and viral replication, it has been demonstrated that several viruses, such as HCV (42) and HBV, stimulate an incomplete autophagy (43) and that autophagy is involved in KSHV replication (15). However, a KSHV protein, K7, expressed during its lytic phase, is able to block the autophagic process (44).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication

Granato

Santarelli

Farina

et al. 2014

J Virol

123

115

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Autophagy is a catabolic pathway that helps cells to survive under stressful conditions. Cells also use autophagy to clear microbiological infections, but microbes have learned how to manipulate the autophagic pathway for their own benefit. The experimental evidence obtained in this study suggests that the autophagic flux is blocked at the final steps during the reactivation of Epstein-Barr virus (EBV) from latency. This is indicated by the level of the lipidated form of LC3 that does not increase in the presence of bafilomycin and by the lack of colocalization of autophagosomes with lysosomes, which correlates with reduced Rab7 expression. Since the inhibition of the early phases of autophagy impaired EBV replication and viral particles were observed in autophagic vesicles in the cytoplasm of producing cells, we suggest that EBV exploits the autophagic machinery for its transportation in order to enhance viral production. The autophagic block was not mediated by ZEBRA, an immediate-early EBV lytic gene, whose transfection in Ramos, Akata, and 293 cells promoted a complete autophagic flux. The block occurred only when the complete set of EBV lytic genes was expressed. We suggest that the inhibition of the early autophagic steps or finding strategies to overcome the autophagic block, allowing viral degradation into the lysosomes, can be exploited to manipulate EBV replication. IMPORTANCEThis study shows, for the first time, that autophagy is blocked at the final degradative steps during EBV replication in several cell types. Through this block, EBV hijacks the autophagic vesicles for its intracellular transportation and enhances viral production. A better understanding of virus-host interactions could help in the design of new therapeutic approaches against EBV-associated malignancies.

show abstract

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication

Granato

Santarelli

Farina

et al. 2014

J Virol

123

115

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show abstract

“…Recent studies by Ke andChen (2011) andShrivastava et al (2011) have revealed that hepatitis C virus (HCV)-induced autophagic pathway suppresses the innate immune response, leading to HCV replication. HCV, a positive ssRNA enveloped virus, induces complete autophagy through activation of the unfolded protein response (UPR), which positively regulates HCV RNA replication.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, HCV infection in autophagy-knockdown immortalized human hepatocytes (IHHs) enhances the IFN signaling pathway and reduces viral replication. Beclin 1 or Atg7 knock-down IHHs infected with HCV, exhibit increased expression of IFN-regulated genes, including IFN-α/β, 2'5'-oligoadenylate synthetase 1 and IFN-α-inducible protein 27 (IFI27) mRNAs (Shrivastava et al 2011).…”

Section: Discussionmentioning

confidence: 99%

In vivo induction of autophagy in splenocytes of C57BL/6 and BALB/c mice infected with ectromelia orthopoxvirus

Martyniszyn

Szulc-Dąbrowska

Boratyńska-Jasińska

et al. 2013

Polish Journal of Veterinary Sciences

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Autophagy is a self-degradation process of cellular components. It plays both antiviral and pro-viral roles in the life cycle of different viruses and the pathogenesis of different viral diseases. In this study, we evaluated autophagy induction in splenocytes of ectromelia virus (ECTV)-resistant C57BL/6 and ECTV-susceptible BALB/c mice during infection with the Moscow strain of the ectromelia virus (ECTV-MOS). Autophagy was analyzed using the Western blot method by assessing type II microtubule-associated protein 1 (MAP1) light chain 3 (LC3) and Beclin 1 expression levels relative to β-actin. Results indicated an increased ratio of LC3-II to β-actin in splenocytes of C57BL/6 mice only at 7 day post infection (d.p.i.) compared to uninfected animals. LC3-II/β-actin and Beclin 1/β-actin ratios in splenocytes of BALB/c mice increased at 5 d.p.i. and remained high until day 14 and 7 p.i., respectively. We confirmed the formation of autophagosome structures in the spleen of BALB/c mice by transmission electron microscopy (TEM). Moreover, autophagy accompanied necrosis in the splenocytes of infected animals. Results suggest that ECTV-MOS induced autophagy, especially in the spleen of the susceptible mouse strain, may support viral replication and promote cell necrosis.

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“…Importantly, viruses can manipulate the autophagic pathway in order to promote different aspects of the viral replication cycle, ranging from virus entry up to egress (16). It is well established that positive-strand RNA viruses utilize autophagy to promote viral RNA translation, RNA replication, and virus particle production (17)(18)(19)(20)(21)(22)(23)(24). Several lines of evidence suggest a proviral role of autophagy during DENV infection.…”

mentioning

confidence: 99%

Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62

Metz

Chiramel

Chatel‐Chaix

et al. 2015

J Virol

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Autophagic flux involves formation of autophagosomes and their degradation by lysosomes. Autophagy can either promote or restrict viral replication. In the case of Dengue virus (DENV), several studies report that autophagy supports the viral replication cycle, and describe an increase of autophagic vesicles (AVs) following infection. However, it is unknown how autophagic flux is altered to result in increased AVs. To address this question and gain insight into the role of autophagy during DENV infection, we established an unbiased, image-based flow cytometry approach to quantify autophagic flux under normal growth conditions and in response to activation by nutrient deprivation or the mTOR inhibitor Torin1. We found that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Early after infection, basal and activated autophagic flux was enhanced. However, during established replication, basal and Torin1-activated autophagic flux was blocked, while autophagic flux activated by nutrient deprivation was reduced, indicating a block to AV formation and reduced AV degradation capacity. During late infection AV levels increased as a result of inefficient fusion of autophagosomes with lysosomes. In addition, endolysosomal trafficking was suppressed, while lysosomal activities were increased. We further determined that DENV infection progressively reduced levels of the autophagy receptor SQSTM1/p62 via proteasomal degradation. Importantly, stable overexpression of p62 significantly suppressed DENV replication, suggesting a novel role for p62 as a viral restriction factor. Overall, our findings indicate that in the course of DENV infection, autophagy shifts from a supporting to an antiviral role, which is countered by DENV. IMPORTANCEAutophagic flux is a dynamic process starting with the formation of autophagosomes and ending with their degradation after fusion with lysosomes. Autophagy impacts the replication cycle of many viruses. However, thus far the dynamics of autophagy in case of Dengue virus (DENV) infections has not been systematically quantified. Therefore, we used high-content, imaging-based flow cytometry to quantify autophagic flux and endolysosomal trafficking in response to DENV infection. We report that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Further, lysosomal activity was increased, but endolysosomal trafficking was suppressed confirming the block of autophagic flux. Importantly, we provide evidence that p62, an autophagy receptor, restrict DENV replication and was specifically depleted in DENV-infected cells via increased proteasomal degradation. These results suggest that during DENV infection autophagy shifts from a proviral to an antiviral cellular process, which is counteracted by the virus. Dengue virus (DENV) is a member of the family Flaviviridae and is responsible for one of the most common infections transmitted to humans by mosquitoes. DENV is a positive-st...

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Knockdown of autophagy enhances the innate immune response in hepatitis C virus-infected hepatocytes

Cited by 180 publications

References 40 publications

Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication

Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication

In vivo induction of autophagy in splenocytes of C57BL/6 and BALB/c mice infected with ectromelia orthopoxvirus

Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62

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