Activation of endoplasmic reticulum stress response by hepatitis C virus proteins

Abstract

Flaviviruses utilize the endoplasmic reticulum (ER) as the main site for replication and protein synthesis and cause some level of ER stress. In the present study, we evaluated the ability of HCV proteins to induce ER stress response by using a tetracycline-regulated cell line expressing a region of HCV genome containing the structural genes. In this system different levels of HCV protein expression could be obtained by varying the concentration of tetracycline in the medium. Real Time PCR and Western blotting assay demonstrated that HCV mRNA and protein levels reach a maximum value at 24-48 h and decrease at 72 h postinduction. Cell proliferation analysis indicated that HCV synthesis causes cell growth inhibition. The effect was also observed in cells expressing lower levels of HCV proteins. The expression profile of specific genes, which are markers of ER stress response, revealed the upregulation of the chaperone GRP78 and the transcription factor GADD153. Induction of GADD153 correlates with the downregulation of the antiapoptotic Bcl-2 gene suggesting that synthesis of HCV proteins may influence cell fate through the activation of ER stress signaling pathway.

KDEL-Retained Antigen in B Lymphocytes Induces a Proinflammatory Response: A Possible Role for Endoplasmic Reticulum Stress in Adaptive T Cell Immunity

“…As such, the molecular and genome-wide studies presented herein may have important implications to better understand the adaptive immune response against ER stress-inducing viruses, such as hepatitis C virus (51), and against cancer cells in which ER stress has been documented (52). Because a proinflammatory response dominated by IL-23 has been recently linked with the pathogenesis of certain autoimmune diseases (53) and IL-23 seems to be required for inflammatory responses against bacterial and mycobacterial infection (54, 55), our findings are relevant to better understand the nexus between infection and immune pathology.…”

Divergent Roles of IRE1α and PERK in the Unfolded Protein Response

“…shielding of hydrophobic amino acid residues from surrounding water, is a major [313,314] Herpes simplex virus 1 PERK PO 4 3-↑, eIF2α PO 4 3-attenuated by γ 1 34.5 protein [315] driving force in protein folding [35]. Protein folding occurs on a µs to ms time scale [36], whereas messenger ribonucleic acids (mRNAs) are translated at 2-8 amino acids/s [37].…”

How Positive-Strand RNA Viruses Benefit from Autophagosome Maturation

“…This effect is due to the degradation of protein aggregates and misfolded proteins (90). Both HCV and EMCV have been shown to increase ER stress (68,69,(93)(94)(95). By allowing autophagic degradation to proceed unperturbed, these viruses may be minimizing the risk of cell death prior to the completion of the replicative cycle.…”