Distinct functional role of Hepatitis C virus core protein on NF-kappaB regulation is linked to genomic variation.
Hepatitis C virus (HCV) often causes a prolonged and persistent infection. Sequence divergence in the HCV genome indicates several genotypes and a series of subtypes for this virus. The core protein of HCV has many intriguing functional properties and is implicated as a factor in virus mediated pathogenesis. Nuclear factor kappaB (NF-kappaB), a transcription factor, responds to inflammatory signals, activates the expression of inflammatory mediators, and plays a role in cell proliferation process. In this study, we have investigated NF-kappaB regulation by HCV core protein cloned from three isolates of different genotypes. Our results suggest that core protein from HCV genotype 1a represses NF-kappaB activation, unlike two other core genomic regions from HCV genotype 1b (BK or Taiwan). However, missense mutations in positions (K(9) to R or N(11) to T) of HCV genotype 1a relieve repression of NF-kappaB regulation by core protein. Interestingly, in vitro translation studies suggested that amino acid substitution at position 11 (N-->T) in HCV genotype 1a generated a primary protein product of approximately 17 kDa, smaller than the major approximately 21 kDa protein band apparent in the parental sequence or with one carrying mutation at amino acid position 9 (K-->R). However, the approximately 17 kDa protein did not appear to be involved in NF-kappaB regulation. Taken together, our present data suggest that genomic variation in the core protein determines a distinct functional regulation of NF-kappaB, which may modulate immunnoregulatory molecules early in viral infection.
Ray
Ratna B
RB
Department of Pathology, Saint Louis University, St. Louis, MO 63110, USA. rayrb@slu.edu
Steele
Robert
R
Basu
Arnab
A
Meyer
Keith
K
Majumder
Mainak
M
Ghosh
Asish K
AK
Ray
Ranjit
R
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001216:Asparagine / Q000235:genetics / Q000502:physiology; D014644:Genetic Variation; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000276:immunology*; D010455:Peptides; D014176:Protein Biosynthesis; D017386:Sequence Homology, Amino Acid; D013912:Threonine / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology*
D016328:NF-kappa B; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D013912:Threonine; D001216:Asparagine