Activation of the Ca2+/NFAT pathway by assembly of hepatitis C virus core protein into nucleocapsid-like particles

• Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The main virion component the core (C) protein has been implicated in several aspects of HCV pathology including oncogenesis, immune evasion, and stress responses. We and others have previously shown that the expression of C in different cell lines triggers Ca2+ signaling and alters Ca2+ homeostasis. In this study, we have identified two distinct C protein regions required for activation of the Ca2+/NFAT signaling. In the basic N-terminal domain, which has been implicated in the self-association of C, amino acids 1-68 were critical for NFAT activation. Sedimentation analysis of the four mutants in this domain revealed that association of the C protein into nucleocapsid-like particles correlated with NFAT-activated transcription. The internal, lipid droplet-targeting domain, was dispensable for NFAT-activated transcription. Finally, the C-terminal ER-targeting domain was required in extenso for the C protein function. Our results indicate that targeting of HCV C to the ER is a prerequisite, but not sufficient for inducing Ca2+/NFAT signaling. Taken together, our data are consistent with a model whereby proteolytic intermediates of C with intact transmembrane ER-anchor assemble into pore-like structures in the ER membrane. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Infektionsmedicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Infectious Medicine (hsv//eng)

Nyckelord

HCV

core protein

SPP cleavage

ER

calcium

NFAT

virus assembly

nucleocapsid-like particle

Biology with specialization in Molecular Biology

Biologi med inriktning mot molekylärbiologi

Biology with specialization in Microbiology

Biologi med inriktning mot mikrobiologi

Infectious Diseases

Infektionssjukdomar

Medical Virology

Medicinsk virologi

Medical Science

Medicinsk vetenskap

Publikations- och innehållstyp

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