The C-terminal region of hepatitis C core protein is required for Fas-ligand independent apoptosis in Jurkat cells by facilitating Fas oligomerization

Abstract

Hepatitis C virus (HCV) is remarkable for its ability to establish persistent infection. Studies suggest that HCV core protein modulates immune responses to viral infection and can bind Fas receptor in vitro. To further examine the role of HCV core protein in Fas signaling, full-length (aa 1-192) and truncated (aa 1-152) HCV core proteins were expressed in Jurkat lymphocytes and cells were assayed for apoptotic response, caspase activation, and Fas activation. Jurkat expressing full-length but not truncated core protein exhibited ligand-independent apoptosis. Cytoplasmic targeting of truncated core protein recapitulated its ability to induce apoptosis. Activation of caspases 8 and 3 was necessary and sufficient for full-length core to induce apoptosis. Jurkat cells expressing full-length but not truncated core protein induced Fas receptor aggregation. HCV core activates apoptotic pathways in Jurkat via Fas and requires cytoplasmic localization of core. Infection of host lymphocytes by HCV may alter apoptotic signaling and skew host responses to acute infection.

The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1

“…The apoptotic property of the genotype 1a core protein has yet to be studied using the JFH-1-based infectious clone system, although previous studies have attributed both prosurvival and proapoptotic properties to it (25,30,46,57). Similar observations also have been described in overexpression studies using the genotype 1b core protein and appear to be dependent on the death stimuli and types of cells used (3,9,10,36,49,53,56,60,76).…”

“…In addition, other domains in the core protein have been shown to bind host proteins and may contribute to apoptosis regulation by interfering with different cellular pathways (see reviews in references 33, 42, and 52). For example, the Nterminal domain (aa 1 to 75) of the core protein interacts with Hsp60, leading to the production of reactive oxygen species and enhancement of tumor necrosis factor alpha-mediated apoptosis (30), while a C-terminal domain (aa 153 to 192) facilitates Fas oligomerization and is required for apoptosis induction in Jurkat cells (46). However, the relative contribution of these various factors to apoptosis induction during HCV infection remains to be determined.…”

“…Several studies have identified domains or regions within the core protein that interfere with specific apoptosis pathways. For instance, the interaction of the N-terminal domain (residues 1 to 75) of the genotype 1a core protein with Hsp60 enhanced tumor necrosis factor alphamediated apoptosis, while its C-terminal region (residues 153 to 192) is required for Fas ligand-independent apoptosis (30,46). The genotype 1b core protein (residues 1 to 153) binds to the death domain of FADD, resulting in enhanced apoptosis (76).…”

CD47 Augments Fas/CD95-mediated Apoptosis

“…There are several well characterized cases in which expression or modification of intracellular proteins inhibits or promotes apoptotic events downstream of Fas (3,6). In contrast, few examples exist in which Fas activity is modulated in either a positive or negative fashion by membrane proteins expressed in cis (7).…”

The Wild-Type Hepatitis C Virus Core Inhibits Initiation of Antigen-Specific T- and B-Cell Immune Responses in BALB/c Mice

“…Interaction of the HCV core protein with a wide variety of cellular proteins has been reported to influence host cell functions (26,34). The HCV core protein is also able to suppress host immunity through several mechanisms, such as impairment of the function of dendritic cells in vitro, promotion of apoptosis of immune cells, or suppression of type I interferon (IFN) signaling, among other mechanisms (7,14,22,28,31,32,52). In the case of DNA vaccination, a high level of expression of the HCV core protein is desired for the priming of specific immune responses.…”