Hepatitis B Virus Disrupts Mitochondrial Dynamics: Induces Fission and Mitophagy to Attenuate Apoptosis

Kim, Seong-Jun; Khan, Mohsin; Quan, Jun; Till, Andreas; Subramani, Suresh; Siddiqui, Aleem

doi:10.1371/journal.ppat.1003722

Cited by 252 publications

(341 citation statements)

References 51 publications

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“…48 HBV infection can promote PARK2/parkin-mediated mitochondrial autophagy (mitophagy) to eliminate damaged mitochondria and attenuate apoptosis of virus-infected cells. 49 In our study, inhibition of autophagy sensitized HBV-infected cells to TNFSF10-mediated killing by restoring the TNFRSF10B level without affecting CASP8 or CASP3. Taken together, the data suggest that HBx-induced autophagy contributes to the protection of virus-infected hepatocytes from TNFSF10-mediated apoptosis.…”

Section: 23supporting

confidence: 51%

Hepatitis B virus–triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response

et al. 2016

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Death receptors of TNFSF10/TRAIL (tumor necrosis factor superfamily member 10) contribute to immune surveillance against virus-infected or transformed cells by promoting apoptosis. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling, leading to persistent infection. Here, we report that hepatitis B virus (HBV) X protein (HBx) restricts TNFSF10 receptor signaling via macroautophagy/autophagymediated degradation of TNFRSF10B/DR5, a TNFSF10 death receptor, and thus permits survival of virusinfected cells. We demonstrate that the expression of the TNFRSF10B protein is dramatically reduced both in liver tissues of chronic hepatitis B patients and in cell lines transfected with HBV or HBx. HBx-mediated downregulation of TNFRSF10B is caused by the lysosomal, but not proteasomal, degradation pathway. Immunoblotting analysis of LC3B and SQSTM1, and microscopy analysis of tandem-fluorescence-tagged LC3B revealed that HBx promotes complete autophagy. Inhibition of autophagy with a pharmacological inhibitor and LC3B knockdown revealed that HBx-induced autophagy is crucial for TNFRSF10B degradation. Immunoprecipitation and GST affinity isolation assays showed that HBx directly interacts with TNFRSF10B and recruits it to phagophores, the precursors to autophagosomes. We confirmed that autophagy activation is related to the downregulation of the TNFRSF10B protein in liver tissues of chronic hepatitis B patients. Inhibition of autophagy enhanced the susceptibility of HBx-infected hepatocytes to TNFSF10. These results identify the dual function of HBx in TNFRSF10B degradation: HBx plays a role as an autophagy receptor-like molecule, which promotes the association of TNFRSF10B with LC3B; HBx is also an autophagy inducer. Our data suggest a molecular mechanism for HBV evasion from TNFSF10-mediated antiviral immunity, which may contribute to chronic HBV infection.

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Section: 23supporting

confidence: 51%

Hepatitis B virus–triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response

et al. 2016

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“…However, HCV-induced aberrant mitochondrial dynamics may also contribute to the viral persistence by attenuating apoptosis of infected cells. A similar strategy of perturbation of mitochondrial dynamics and attenuation of apoptosis is also used by hepatitis B virus (29). Our findings implicate the mitochondrial quality control pathway as a potential therapeutic target against HCV infection and associated liver disease pathogenesis.…”

Section: Discussionmentioning

confidence: 62%

“…The pEGFP-LC3 plasmid DNA was a kind gift from Tamotsu Yoshimori (National Institute of Genetics, Japan). The p-mito-mRFP-EGFP plasmid DNA (pAT016) was described previously (29).…”

Section: Methodsmentioning

confidence: 99%

“…To examine whether Drp1-mediated mitochondrial fission facilitates mitophagy in HCV-infected cells, we used a tandem-tagged mRFP-EGFP chimeric fluorescence reporter (plasmid pAT016) encoding a mitochondrial targeting signal sequence fused inframe with mRFP and EGFP genes (SI Appendix, Fig. S4) (29). The use of this expression scheme exploits the differential stabilities of RFP and GFP in the lysosomes (SI Appendix, Fig.…”

Section: Hcv Induces Drp1 Ser616 Phosphorylation and Mitochondrialmentioning

confidence: 99%

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Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence

Kim

Syed

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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239

272

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Mitochondrial dynamics is crucial for the regulation of cell homeostasis. Our recent findings suggest that hepatitis C virus (HCV) promotes Parkin-mediated elimination of damaged mitochondria (mitophagy). Here we show that HCV perturbs mitochondrial dynamics by promoting mitochondrial fission followed by mitophagy, which attenuates HCV-induced apoptosis. HCV infection stimulated expression of dynamin-related protein 1 (Drp1) and its mitochondrial receptor, mitochondrial fission factor. HCV further induced the phosphorylation of Drp1 (Ser616) and caused its subsequent translocation to the mitochondria, followed by mitophagy. Interference of HCV-induced mitochondrial fission and mitophagy by Drp1 silencing suppressed HCV secretion, with a concomitant decrease in cellular glycolysis and ATP levels, as well as enhanced innate immune signaling. More importantly, silencing Drp1 or Parkin caused significant increase in apoptotic signaling, evidenced by increased cytochrome C release from mitochondria, caspase 3 activity, and cleavage of poly(ADP-ribose) polymerase. These results suggest that HCV-induced mitochondrial fission and mitophagy serve to attenuate apoptosis and may contribute to persistent HCV infection.HCV persistence | innate immunity | autophagy H epatitis C virus (HCV) infection often leads to chronic hepatitis that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (1). HCV is a hepatotropic, noncytopathic (2, 3), single-stranded, positive-sense RNA virus that replicates its RNA genome on the endoplasmic reticulum (ER)-derived membranous structures (4, 5). HCV stimulates lipogenesis, leading to the accumulation of lipid droplets that facilitate virion assembly and maturation (5-8). HCV infection also induces mitochondrial dysfunction via ER and oxidative stress that results in mitochondrial Ca 2+ overload, collapse of mitochondrial transmembrane potential (ΔΨm), elevated levels of reactive oxygen species, and disruption of mitochondrial respiration (9-15). Liver tissues of patients with chronic hepatitis C frequently exhibit traits of mitochondrial injury such as swollen, ruptured, and empty mitochondria (16).Mitochondria are dynamic organelles that constantly undergo fission, fusion, and mitophagy to facilitate mitochondrial quality control, which is crucial for maintaining cell viability and bioenergetics (17). Aberrant mitochondrial dynamics are associated with the pathogenesis of several genetic and neurological disorders, cardiac dysfunctions, cancer, and metabolic diseases such as diabetes and obesity (18). Depending on their physiological and cellular context, the balance between mitochondrial fission and fusion processes modulates the mitochondrial morphology (17). Mitochondrial fission/fragmentation is mediated by recruitment of cytosolic Drp1 to the mitochondria, forming spirals that constrict both the inner and outer mitochondrial membranes (19). The mitochondrial fission is modulated by mitochondrial outer membrane proteins, which include mitochondrial fission 1 (Fis1), mitocho...

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“…The p-mito-mRFP-EGFP plasmid was a kind gift of Dr. Siddiqui (University of California, San Diego), which was generated as previously described. 67 …”

Section: Transfections and Dna Constructsmentioning

confidence: 99%

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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Mitochondria are sentinel organelles that are impacted by various forms of cellular stress, including viral infections. While signaling events associated with mitochondria, including those activated by pathogen associated molecular patterns (PAMPs), are widely studied, alterations in mitochondrial distribution and changes in mitochondrial dynamics are also beginning to be associated with cellular insult. Cells of neuronal origin have been demonstrated to display remarkable alterations in several instances, including neurodegenerative disorders. Venezuelan Equine Encephalitis Virus (VEEV) is a New World alphavirus that infects neuronal cells and contributes to an encephalitic phenotype. We demonstrate that upon infection by the vaccine strain of VEEV (TC-83), astrocytoma cells experience a robust drop in mitochondrial activity, which corresponds with an increased accumulation of reactive oxygen species (ROS) in an infection-dependent manner. Infection status also corresponds with a prominent perinuclear accumulation of mitochondria. Cellular enzymatic machinery, including PINK1 and Parkin, appears to be enriched in mitochondrial fractions as compared with uninfected cells, which is indicative of mitochondrial damage. Dynamin related protein 1 (Drp1), a protein that is associated with mitochondrial fission, demonstrated a modest enrichment in mitochondrial fractions of infected cells. Treatment with an inhibitor of mitochondrial fission, Mdivi-1, led to a decrease in caspase cleavage, suggesting that mitochondrial fission was likely to contribute to apoptosis of infected cells. Finally, our data demonstrate that mitophagy ensues in infected cells. In combination, our data suggest that VEEV infection results in significant changes in the mitochondrial landscape that may influence pathological outcomes in the infected cell.

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Hepatitis B Virus Disrupts Mitochondrial Dynamics: Induces Fission and Mitophagy to Attenuate Apoptosis

Cited by 252 publications

References 51 publications

Hepatitis B virus–triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response

Hepatitis B virus–triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response

Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

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