West Nile virus capsid protein interaction with importin and HDM2 protein is regulated by protein kinase C-mediated phosphorylation |
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| Authors: | Raghavan Bhuvanakantham Yuen Kuen Cheong Mah-Lee Ng |
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| Affiliation: | 1. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan;2. Department of Neurology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan;3. Department of Pediatrics, National Taiwan University, Children''s Hospital, Hsinchu, Taiwan;4. Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan;1. Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;2. Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA |
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| Abstract: | West Nile virus (WNV) capsid (C) protein was shown to enter the nucleus via importin-mediated pathway and induce apoptosis although the precise regulatory mechanisms for such events have remained elusive. In this study, it was shown that WNV C protein was phosphorylated by protein kinase C (PKC). PKC-mediated phosphorylation influenced nuclear trafficking of C protein by modulating the efficiency of C protein–importin-α binding. Combination of bio-informatics, site-directed mutagenesis, co-immunoprecipitation, immuno-fluorescence and mammalian two-hybrid analyses showed that phosphorylation at amino acid residues residing near (Ser83) or within (Ser99 and Thr100) the bipartite nuclear localization motif of WNV C protein was essential for efficient interaction between C protein and importin-α. In addition, phosphorylation of WNV C protein by PKC was shown to enhance its binding to HDM2 and could subsequently induce p53-dependent apoptosis. Collectively, this study highlighted that phosphorylation is an important post-translational modification required to execute the functions of C protein. |
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