title: West Nile virus and dengue virus capsid protein negates the antiviral activity of human Sec3 protein through the proteasome pathway.
abstract: Flavivirus capsid (C) protein is a key structural component of virus particles. The non-structural role of C protein in the pathogenesis of arthropod-borne flaviviruses is not clearly deciphered. This study showed that West Nile virus (WNV) and dengue virus (DENV) utilized C protein to reduce human Sec3p (hSec3p) levels at post-transcriptional level through activation of chymotrypsin-like proteolytic function of 20S proteasome. Mutagenesis studies confirmed amino acids 14, 109-114 of WNV C protein and 13, 102-107 of DENV C protein played an important role in activating the proteolytic function of 20S proteasome. Amino acid residues at 14 (WNV) and 13 (DENV) of C protein were important for C protein-hSec3p binding and physical interaction between C protein and hSec3p was essential to execute hSec3p degradation. Degradation motif required to degrade hSec3p resided between amino acid residues 109-114 of WNV C protein and 102-107 of DENV C protein. Proteasomes, hSec3p binding motif and degradation motif on C protein must be intact for efficient flavivirus production. Clinical isolates of DENV showed more pronounced effect in manipulating the proteasomes and reducing hSec3p levels. This study portrayed the non-structural function of C protein that helped the flavivirus to nullify the antiviral activity of hSec3p by accelerating its degradation and facilitating efficient binding of elongation factor 1α with flaviviral RNA genome.
authors.affiliation: Flavivirology Laboratory, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore, 117597.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Bhuvanakantham
authors.forename: Mah-Lee
authors.initials: ML
authors.lastname: Ng
mesh_terms: D000998:Antiviral Agents / Q000037:antagonists & inhibitors*; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004252:DNA Mutational Analysis; D003716:Dengue Virus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D059748:Proteolysis; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors*; D014902:West Nile virus / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D046988:Proteasome Endopeptidase Complex; D033921:Vesicular Transport Proteins; C529992:EXOC1 protein, human