| First Author | Kao YT | Year | 2015 |
| Journal | PLoS Pathog | Volume | 11 |
| Issue | 3 | Pages | e1004750 |
| PubMed ID | 25816318 | Mgi Jnum | J:246600 |
| Mgi Id | MGI:5916680 | Doi | 10.1371/journal.ppat.1004750 |
| Citation | Kao YT, et al. (2015) Japanese encephalitis virus nonstructural protein NS5 interacts with mitochondrial trifunctional protein and impairs fatty acid beta-oxidation. PLoS Pathog 11(3):e1004750 |
| abstractText | Infection with Japanese encephalitis virus (JEV) can induce the expression of pro-inflammatory cytokines and cause acute encephalitis in humans. beta-oxidation breaks down fatty acids for ATP production in mitochondria, and impaired beta-oxidation can induce pro-inflammatory cytokine expression. To address the role of fatty-acid beta-oxidation in JEV infection, we measured the oxygen consumption rate of mock- and JEV-infected cells cultured with or without long chain fatty acid (LCFA) palmitate. Cells with JEV infection showed impaired LCFA beta-oxidation and increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) expression. JEV nonstructural protein 5 (NS5) interacted with hydroxyacyl-CoA dehydrogenase alpha and beta subunits, two components of the mitochondrial trifunctional protein (MTP) involved in LCFA beta-oxidation, and NS5 proteins were detected in mitochondria and co-localized with MTP. LCFA beta-oxidation was impaired and higher cytokines were induced in cells overexpressing NS5 protein as compared with control cells. Deletion and mutation studies showed that the N-terminus of NS5 was involved in the MTP association, and a single point mutation of NS5 residue 19 from methionine to alanine (NS5-M19A) reduced its binding ability with MTP. The recombinant JEV with NS5-M19A mutation (JEV-NS5-M19A) was less able to block LCFA beta-oxidation and induced lower levels of IL-6 and TNF-alpha than wild-type JEV. Moreover, mice challenged with JEV-NS5-M19A showed less neurovirulence and neuroinvasiveness. We identified a novel function of JEV NS5 in viral pathogenesis by impairing LCFA beta-oxidation and inducing cytokine expression by association with MTP. |
