Hepatitis C Virus NS5A and Subgenomic Replicon Activate NF-κB via Tyrosine Phosphorylation of IκBα and Its Degradation by Calpain Protease

Waris, Gulam; Livolsi, Antonia; Imbert, Véronique; Peyron, Jean‐François; Siddiqui, Aleem

doi:10.1074/jbc.m303248200

Cited by 111 publications

(106 citation statements)

References 61 publications

(84 reference statements)

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“…32 We have confirmed and extended these results: while a strong increase of calpainlike activity occurred upon the expression both of the full complement of viral proteins, the nonstructural subset, or specifically the NS5A of the 1b and the 1a HCV genotypes, the 2a genotype protein had no effect either on calpain activity or on the stability of the Bid protein.…”

Section: Discussionsupporting

confidence: 72%

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #

et al. 2009

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An unresolved question regarding the physiopathology of hepatitis C virus (HCV) infection is the remarkable efficiency with which host defenses are neutralized to establish chronic infection. Modulation of an apoptotic response is one strategy used by viruses to escape immune surveillance. We previously showed that HCV proteins down-regulate expression of BH3-only Bcl2 interacting domain (Bid) in hepatocytes of HCV transgenic mice. As a consequence, cells acquire resistance to Fas-mediated apoptosis, which in turn leads to increased persistence of experimental viral infections in vivo. This mechanism might participate in the establishment of chronic infections and the resulting pathologies, including hepatocellular carcinoma. We now report that Bid is also down-regulated in patients in the context of noncirrhotic HCV-linked tumorigenesis and in the HCV RNA replicon system. We show that the nonstructural HCV viral protein NS5A is sufficient to activate a calpain cysteine protease, leading to degradation of Bid. Moreover, pharmacological inhibitors of calpains restore both the physiological levels of Bid and the sensitivity of cells toward a death receptor-mediated apoptotic signal. Finally, human HCV-related tumors and hepatocytes from HCV transgenic mice that display low Bid expression contain activated calpains. Conclusion: Calpains activated by HCV proteins degrade Bid and thus dampen apoptotic signaling. These results suggest that inhibiting calpains could lead to an improved efficiency of immune-mediated elimination of HCV-infected cells. (HEPATOLOGY 2009;50:1370-1379.)P ersistent infection with hepatitis C virus (HCV) is among the most common infectious causes of chronic liver disease. The majority of patients fail to clear the virus and become chronic carriers, with a persistent presence of detectable virus in the serum. 1 Patients with chronic hepatitis C are at risk for hepatic fibrosis, frequently culminating in hepatic cirrhosis and hepatocellular carcinoma (HCC). 2 FL-N/35 transgenic mice, with hepatocyte-targeted expression of the entire open reading frame of the genotype 1b HCV, are at risk for steatosis and hepatocellular adenoma and carcinoma. 3 We previously showed that the FL-N/35 hepatocytes are resistant to apoptosis induced by the Fas/CD95 death receptor stimulation. The lack of sensitivity to apoptotic stimulation was related to decreased expression of BH3-only Bcl2 interacting domain (Bid), a BH3-only member of the Bcl-2 family of apoptosis regulators. 4 Importantly, Bid-deficient hepatocytes are refractory to T lymphocyte-induced cell death, suggesting that apoptosis contributes to HCV persistence and, as a consequence, to liver pathologies characteristic of chronic HCV infection. 4 Here, we report that Bid is also down-regulated in the context of the subgenomic and genome-length HCV replicons and in a subset of HCV-linked human HCC.

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Section: Discussionsupporting

confidence: 72%

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #

et al. 2009

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“…Like EBV, cancers caused by hepatitis B, C, and human T cell lymphotropic virus have a high frequency of p16ink4a hypermethylation (40,41). Also, viral structural proteins, such as HBX of hepatitis B, HCV NS3, NS5, and human T cell lymphotropic virus tax protein, are known to induce reactive oxygen (42)(43)(44)(45). Reactive oxygen may play a decisive role in carcinogenesis in potentially most virally induced human cancers, and it may serve as a pharmacologic target for chemoprevention and treatment.…”

Section: Differential Inhibition Of Nf-b Signaling By Inhibition Of Pmentioning

confidence: 99%

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Cerimele

Battle²,

Lynch³

et al. 2004

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

138

137

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Burkitt's lymphoma (BL) is an aggressive B cell neoplasm, which is one of the most common neoplasms of childhood. It is highly widespread in East Africa, where it appears in endemic form associated with Epstein-Barr virus (EBV) infection, and around the world in a sporadic form in which EBV infection is much less common. In addition to being the first human neoplasm to be associated with EBV, BL is associated with a characteristic translocation, in which the Ig promoter is translocated to constitutively activate the c-myc oncogene. Although many BLs respond well to chemotherapy, a significant fraction fails to respond to therapy, leading to death. In this article, we demonstrate that EBV-positive BL expresses high levels of activated mitogen-activated protein kinase and reactive oxygen species (ROS), and that ROS directly regulate NF-B activation. EBV-negative BLs exhibit activation of phosphoinositol 3-kinase, but do not have elevated levels of ROS. Elevated reactive oxygen may play a role in diverse forms of viral carcinogenesis in humans, including cancers caused by EBV, hepatitis B, C, and human T cell lymphotropic virus. Our findings imply that inhibition of ROS may be useful in the treatment of EBVinduced neoplasia.angiogenesis B urkitt's lymphoma (BL) is a distinct neoplasm of B lymphocytes characterized by a translocation of the Ig heavy-or light-chain promoter and enhancer elements into the c-myc oncogene (1). This neoplasm is also of historic interest, because a technician who developed infectious mononucleosis became seropositive for Epstein-Barr virus (EBV), thus establishing a role of EBV in both acute infectious mononucleosis and BL (1). Since the recognition of a causative role of EBV in infectious mononucleosis, EBV has been implicated in other neoplastic disorders, including nasopharyngeal carcinoma, transplantrelated lymphoproliferative disorder, Hodgkins disease, gastric cancer, and cutaneous leiomyosarcoma in patients with AIDS (2-9).BL is characterized by EBV-positive and -negative phenotypes, which occur in distinct epidemiological subgroups. Endemic BL, which was first characterized as a childhood neoplasm in East Africa, is characterized by rapidly growing tumors of the mandible. EBV-positive BL also occurs at a high frequency in iatrogenically immunosuppressed patients as well as patients who are positive for HIV. Although BLs are often highly responsive to conventional chemotherapy, severe preexisting immunosuppression and other comorbid conditions often prevent full use of chemotherapy in these patients (10).We have previously hypothesized that tumors that exhibit loss of the tumor suppressor genes p16ink4a and͞or p53 also exhibit distinct and predictable patterns of signal transduction pathway dependence (11,12). Based on prior results from our laboratory, we have demonstrated synergy between inactivation of p16ink4a and activation of mitogen-activated protein kinase (MAPK) (13-15). Also, we have found that cancers caused by reactive oxygen species (ROS) demonstrate high levels of hyp...

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“…In this pathway, the b subunit of the IkB kinase (IKK) complex phosphorylates IkBa on two N-terminal conserved serines , leading to its polyubiquitination and subsequent proteasomal degradation (Hayden and Ghosh, 2004). Recently, an alternative proteasome-independent and calpain-dependent mechanism of proteolytic IkBa degradation has also been described (Miyamoto et al, 1998;Han et al, 1999;Pianetti et al, 2001;Kouba et al, 2001;Berry et al, 2002;Waris et al, 2003). Once liberated from IkBa, NF-kB dimers translocate to the nucleus, where they regulate transcription of target genes.…”

Section: Introductionmentioning

confidence: 99%

Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

et al. 2005

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All-trans retinoic acid (ATRA) significantly improves the survival of patients with acute promyelocytic leukemia (APL) by inducing granulocytic differentiation of leukemia cells. Since an activation of the transcription factor NF-jB occurs during ATRA-induced maturation of APL cells, a mechanistic link between these two processes was investigated. Using an in vitro model for APL, we report that ectopic overexpression of a repressor of NF-jB activation did not affect granulocytic differentiation. Importantly, NF-jB inhibition markedly resulted in a decreased viability of the differentiated cells, which correlated with increased apoptosis. Apoptosis was accompanied by a sustained activation of the c-Jun N-terminal kinase (JNK). Inhibition of JNK by the specific inhibitor SP600125 or by transfection of a dominant-negative mutant of JNK1 reduced the percentage of apoptotic cells, thus showing that JNK activation constitutes a death signal. Furthermore, impairment of NF-jB activation resulted in increased levels of reactive oxygen species (ROS) upon ATRA treatment. ROS accumulation was suppressed by the antioxidant butylated hydroxyanisol, which also abolished ATRA-induced JNK activation and apoptosis. Altogether, our results demonstrate an antiapoptotic effect of NF-jB activation during ATRA-induced differentiation of NB4 cells and identify repression of ROS-mediated JNK activation as a mechanism for this effect. Our observations also suggest that NF-jB signalling may contribute to an accumulation of mature APL cells and participate in the development of ATRA syndrome. Oncogene (2005) 24, 7145-7155.

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Hepatitis C Virus NS5A and Subgenomic Replicon Activate NF-κB via Tyrosine Phosphorylation of IκBα and Its Degradation by Calpain Protease

Cited by 111 publications

References 61 publications

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

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