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

Simonin, Y.; Disson, O.; Lerat, H.; Antoine, E.; Biname, F.; Rosenberg, A. R.; Desagher, S.; Lassus, P.; Bioulac-Sage, P.; Hibner, U.


2009-11 / vol 50 / pages 1370-9


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.

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1527-3350 (Electronic) 0270-9139 (Linking)

IGMM team(s) involved in this publication

Apoptosis/*physiology; Female; Humans; Animals; Cells, Cultured; Mice; Male; Disease Models, Animal; Mice, Transgenic; Viral Proteins/*metabolism; Hepacivirus/*metabolism; Adult; Middle Aged; Aged; BH3 Interacting Domain Death Agonist Protein/metabolism; Calpain/*metabolism; Carcinoma, Hepatocellular/metabolism/*pathology; Hepatitis C, Chronic/pathology/physiopathology; Liver Neoplasms/metabolism/*pathology; Liver/metabolism/pathology; Replicon/physiology; Signal Transduction/*physiology; Viral Nonstructural Proteins/metabolism

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