HCV core protein localizes in the nuclei of nonparenchymal liver cells from chronically HCV-infected patients

Falcón, Viviana; Acosta‐Rivero, Nelson; Shibayama, Mineko; Chinea, Glay; Gavilondo, Jorge V.; Rosa, Maria Cristina; Menéndez, Ivón; Gra, Bienvenido; Dueñas‐Carrera, Santiago; Viña, Ariel; Garcı́a, Waldo; González-Bravo, Maritza; Luna-Muñoz, José; Miranda-Sanchez, Magdalena; Morales-Grillo, Juan; Kourí, Juan B.; Tsutsumi, Vı́ctor

doi:10.1016/j.bbrc.2005.02.107

Cited by 21 publications

(20 citation statements)

References 62 publications

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“…These data probably suggest that the activation of HSCs in chronic HCV infection may result from two different pathways: the predominant one involves the necroinflammation as a collateral liver injury that stimulates neighboring HSCs; additionally, HCV also may directly activate HSCs. Several recent studies have suggested a direct profibrogenic potential of HCV: HCV-replicating hepatoma cell lines can secret profibrogenic factors, mainly transforming growth factor b1 [25]; HCV core protein was shown to localize in HSCs of liver biopsies from HCV-infected patients [26]; HCV core and nonstructural proteins can regulate distinct biologic functions of HSCs in vitro [27]. Interestingly, the present results showed that the HSC activation index correlated marginally significantly (P = 0.08) with serum titers of HCV RNA in chronic HCV infection (Table 3), but not with serum tiers of HBV DNA in chronic HBV infection ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

Comparative Studies on Expression of α-Smooth Muscle Actin in Hepatic Stellate Cells in Chronic Hepatitis B and C

Chu¹,

Shyu²,

Liaw³

2007

Dig Dis Sci

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Section: Discussionmentioning

confidence: 99%

Comparative Studies on Expression of α-Smooth Muscle Actin in Hepatic Stellate Cells in Chronic Hepatitis B and C

Chu¹,

Shyu²,

Liaw³

2007

Dig Dis Sci

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“…Indeed, in studies with chimpanzees, no hepatic tran-scription changes are detected during the first weeks of HBV infection, whereas many hepatic transcription changes relating to the type I IFN response are seen upon HCV infection (70). There is debate as to whether macrophages, in addition to hepatocytes, are infected by HCV and support replication (4,9,20,44,69,72,74). If infected, macrophages may also contribute to the early induction of type I IFN signaling through RIG-1 and MDA-5.…”

Section: Macrophage Involvement In Immune Recognition Of Hcv and Hbv mentioning

confidence: 99%

Macrophages in Hepatitis B and Hepatitis C Virus Infections

Heydtmann

2009

J Virol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major health burdens worldwide, with over 300 and 170 million people, respectively, infected. HBV, a DNA virus, and HCV, an RNA virus, are both hepatotropic, and both lead to hepatitis in many patients, with potentially fatal complications, including hepatocellular carcinoma. A high proportion of HCV-and HBV-infected patients develop chronic infections characterized by absent, weak, or narrowly focused T-cell responses (70). It is likely that early immune avoidance mechanisms contribute to the disturbed T-cell responses in combination with various other strategies reviewed elsewhere (7,28,31,36,70,82). The two viruses differ considerably in their interactions with the host immune system, but all current treatment protocols aimed at clearing either virus include alpha interferon (IFN-␣). This implies that the innate immune system is of pivotal importance in the development and maintenance of chronic infection versus viral clearance.Critical components of the innate immune response are liver macrophages. Here we highlight their key roles in both the favorable and adverse responses to HBV and HCV infections.

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“…Because cleavage by SPP removes the C-terminal anchor of core protein, it loosens its attachment to the ER membrane and allows it to travel to other organelles within the cell. Indeed, a characteristic feature of the intracellular distribution of HCV core protein is its association with the surface of lipid droplets (10,(23)(24)(25)(26)(27). This was demonstrated not only in a variety of tissue culture cells, but also in liver biopsies from HCV-infected patients and chimpanzees.…”

mentioning

confidence: 90%

Signal Peptide Peptidase-catalyzed Cleavage of Hepatitis C Virus Core Protein Is Dispensable for Virus Budding but Destabilizes the Viral Capsid

Vauloup‐Fellous

Pène

Garaud-Aunis

et al. 2006

Journal of Biological Chemistry

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The capsid of hepatitis C virus (HCV) particles is considered to be composed of the mature form (p21) of core protein. Maturation to p21 involves cleavage of the transmembrane domain of the precursor form (p23) of core protein by signal peptide peptidase (SPP), a cellular protease embedded in the endoplasmic reticulum membrane. Here we have addressed whether SPP-catalyzed maturation to p21 is a prerequisite for HCV particle morphogenesis in the endoplasmic reticulum. HCV structural proteins were expressed by using recombinant Semliki Forest virus replicon in mammalian cells or recombinant baculovirus in insect cells, because these systems have been shown to allow the visualization of HCV budding events and the isolation of HCV-like particles, respectively. Inhibition of SPP-catalyzed cleavage of core protein by either an SPP inhibitor or HCV core mutations not only did not prevent but instead tended to facilitate the observation of viral buds and the recovery of virus-like particles. Remarkably, although maturation to p21 was only partially inhibited by mutations in insect cells, p23 was the only form of core protein found in HCV-like particles. Finally, newly developed assays demonstrated that p23 capsids are more stable than p21 capsids. These results show that SPP-catalyzed cleavage of core protein is dispensable for HCV budding but decreases the stability of the viral capsid. We propose a model in which p23 is the form of HCV core protein committed to virus assembly, and cleavage by SPP occurs during and/or after virus budding to predispose the capsid to subsequent disassembly in a new cell. Signal peptide peptidase (SPP)5 belongs to a novel family of polytopic membrane-associated aspartyl proteases that catalyze cleavage of peptide bonds within the hydrophobic environment of a lipid bilayer (for review see Ref. 1). SPP is highly conserved in higher eucaryotes from plants to humans, including insects (2, 3). This membrane protein with nine proposed transmembrane domains exerts its action in the endoplasmic reticulum (ER), where it resides by virtue of a classical ER retrieval signal (3-5). The SPP substrates identified so far have in common a type II (N terminus facing the cytosol and C terminus facing the lumen) orientation but do not unequivocally point to a common role for SPP activity. In humans, SPP carries out the intramembrane cleavage of signal peptides of polymorphic major histocompatibility complex class I molecules after they have been cleaved off by signal peptidase; the short N-terminal signal peptide remnants then serve as epitopes presented at the cell surface by nonpolymorphic human lymphocyte antigen-E molecules for immune surveillance (6). Thus, SPP activity may promote the liberation from the ER lipid bilayer of some bioactive signal peptide fragments. Another role of SPP activity may be to protect cells from the toxicity of some signal peptides, e.g. the signal peptide of eosinophil cationic protein (7). Finally, the substrate spectrum of SPP may not be restricted to signal peptides but e...

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HCV core protein localizes in the nuclei of nonparenchymal liver cells from chronically HCV-infected patients

Cited by 21 publications

References 62 publications

Comparative Studies on Expression of α-Smooth Muscle Actin in Hepatic Stellate Cells in Chronic Hepatitis B and C

Comparative Studies on Expression of α-Smooth Muscle Actin in Hepatic Stellate Cells in Chronic Hepatitis B and C

Macrophages in Hepatitis B and Hepatitis C Virus Infections

Signal Peptide Peptidase-catalyzed Cleavage of Hepatitis C Virus Core Protein Is Dispensable for Virus Budding but Destabilizes the Viral Capsid

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