HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis

Deng, Lin; Chen, Ming; Tanaka, Motofumi; Ku, Yonson; Itoh, Tomoo; Shoji, Ikuo; Hotta, Hak

doi:10.1099/jgv.0.000221

Cited by 26 publications

(15 citation statements)

References 56 publications

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“…The ROS/JNK signaling pathway has been shown to upregulate Bim and lead to Bax-mediated apoptosis. 28 Indeed, NAC reduced ROS production (Figure 8b) and Bim expression (Figure 8g), supporting the hypothesis that the ROS-Bim pathway is one of the major cause of apoptosis in Tsc1-deficient DCs. Taken together, Tsc1 promotes DC survival via the independently repression of the mTORC1 and ROS-Bim pathways.…”

Section: Resultssupporting

confidence: 77%

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

Luo

et al. 2017

Cell Death Dis

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Dendritic cells (DCs) are pivotal to the induction of adaptive T-cell immune responses. Recent evidence highlights a critical role of tuberous sclerosis complex 1 (Tsc1), a primarily upstream negative regulator of mammalian target of rapamycin (mTOR), in DC development, but whether and how Tsc1 directly regulate mature DC function in vivo remains elusive. Here we show that selective disruption of Tsc1 in DCs results in a lymphoproliferative disorder with the spontaneous activation of T cells. Tsc1 deficiency results in the activation of mTORC1-PPARγ pathway, which leads to the upregulation of neuropilin-1 (Nrp1) expression on DCs to stimulate naive T-cell proliferation. However, Tsc1-deficient DCs have defects in the ability to induce antigen-specific T-cell responses in vitro and in vivo owing to impaired survival during antigen transportation and presentation. Indeed, Tsc1 promotes DC survival through restraining independent mTORC1 and ROS-Bim pathways. Our study identifies Tsc1 as a crucial signaling checkpoint in DCs essential for preserving T-cell homeostasis and response.

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Section: Resultssupporting

confidence: 77%

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

Luo

et al. 2017

Cell Death Dis

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“…This should be further examined in future experiments. Interestingly, recent observations have shown that infection with HCV-2a alone may induce activation of JNK/Bim and apoptosis in Huh-7.5 cells, although we did not observe increased JNK or Bim activation in OR6 cells without palmitate treatment [ 28 ]. Likewise, in our study, constitutive apoptosis was not elevated in OR6 cells compared to cured cells.…”

Section: Discussioncontrasting

confidence: 88%

“…Although prior studies showed sustained activation of JNK in HCV-infected cells, it was unclear how JNK would play a role in lipoapoptosis in this condition [ 28 ]. Here, palmitate treatment triggered phosphorylation of JNK and activation of Bim.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis

et al. 2017

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BackgroundHepatitis C virus (HCV) infection and metabolic diseases including nonalcoholic steatohepatitis (NASH) exhibit a complex interplay. Although free fatty acid-mediated apoptosis is a prominent feature of NASH, the impact of HCV infection on hepatocyte lipotoxicity has remained largely unexplored. The study aimed at identifying whether infection by HCV affected the apoptotic pathway in hepatocytes during fatty acid assault.Material/MethodsOR6 cells, which are derived from human hepatocellular carcinoma Huh-7 cells and harbor a full-length HCV RNA genome replication system, were treated with palmitate. Apoptosis was examined by 4′,6-diamidino-2-phenylindole staining. Activation and expression of JNK, Bim, cIAP-1, and Mcl-1 were examined by immunoblotting. mRNA expression of CHOP, a major player in endoplasmic reticulum stress-mediated apoptosis, was assessed by real-time PCR.ResultsPalmitate-induced hepatocyte apoptosis was significantly enhanced in OR6 cells compared to cured cells, in which the HCV genome had been eradicated by treatment with interferon-α. Although basal expression of CHOP mRNA was enhanced in OR6 cells compared to cured cells, it was similarly upregulated in both cell lines following palmitate treatment. Notably, palmitate-induced JNK phosphorylation was accentuated in OR6 cells compared to cured cells. Inhibition of JNK with SP600125 attenuated palmitate-induced apoptosis. Palmitate-mediated upregulation of BH3-only protein Bim, which acts downstream of JNK, was also enhanced in OR6 cells compared to cured cells. In contrast, Mcl-1 and cIAP-1 were equally reduced in OR6 cells and cured cells following palmitate treatment.ConclusionsThese findings suggest that during lipoapoptosis, HCV infection may enhance hepatocyte toxicity by increasing JNK phosphorylation.

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“…The ROS/JNK signalling has been reported to be important for Bax-mitochondrial apoptotic pathway 43,44 . Thus, we investigate whether Bax is involved in lobaplatin-induced pyroptosis via ROS/JNK signalling.…”

Section: Resultsmentioning

confidence: 99%

Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells

et al. 2019

Cell Death Dis

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Pyroptosis, a form of programmed cell death (PCD), has garnered increasing attention as it relates to innate immunity and diseases. However, the involvement of pyroptosis in the mechanism by which lobaplatin acts against colorectal cancer (CRC) is unclear. Our study revealed that treatment with lobaplatin reduced the viability of HT-29 and HCT116 cells in a dose-dependent manner. Morphologically, HT-29 and HCT116 cells treated with lobaplatin exhibited microscopic features of cell swelling and large bubbles emerging from the plasma membrane, and transmission electron microscopy (TEM) revealed multiple pores in the membrane. GSDME, rather than GSDMD, was cleaved in lobaplatin-induced pyroptosis in HT-29 and HCT116 cells due to caspase-3 activation. Knocking out GSDME switched lobaplatin-induced cell death from pyroptosis to apoptosis but did not affect lobaplatin-mediated inhibition of growth and tumour formation of HT-29 and HCT116 cells in vivo and in vitro. Further investigation indicates that lobaplatin induced reactive oxygen species (ROS) elevation and JNK phosphorylation. NAC, a ROS scavenger, completely reversed the pyroptosis of lobaplatin-treated HT-29 and HCT116 and JNK phosphorylation. Activated JNK recruited Bax to mitochondria, and thereby stimulated cytochrome c release to cytosol, followed by caspase-3/-9 cleavage and pyroptosis induction. Therefore, in colon cancer cells, GSDME mediates lobaplatin-induced pyroptosis downstream of the ROS/JNK/Bax-mitochondrial apoptotic pathway and caspase-3/-9 activation. Our study indicated that GSDME-dependent pyroptosis is an unrecognized mechanism by which lobaplatin eradicates neoplastic cells, which may have important implications for the clinical application of anticancer therapeutics.

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HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis

Cited by 26 publications

References 56 publications

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response

Hepatitis C Virus Infection Increases c-Jun N-Terminal Kinase (JNK) Phosphorylation and Accentuates Hepatocyte Lipoapoptosis

Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells

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