| First Author | García Del Río A | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 10 | Pages | 2977-2985 |
| PubMed ID | 30322967 | Mgi Jnum | J:267730 |
| Mgi Id | MGI:6258115 | Doi | 10.4049/jimmunol.1701075 |
| Citation | Garcia Del Rio A, et al. (2018) The Mitochondrial Isoform of FASTK Modulates Nonopsonic Phagocytosis of Bacteria by Macrophages via Regulation of Respiratory Complex I. J Immunol 201(10):2977-2985 |
| abstractText | Phagocytosis is a pivotal process by which innate immune cells eliminate bacteria. In this study, we explore novel regulatory mechanisms of phagocytosis driven by the mitochondria. Fas-activated serine/threonine kinase (FASTK) is an RNA-binding protein with two isoforms, one localized to the mitochondria (mitoFASTK) and the other isoform to cytosol and nucleus. The mitoFASTK isoform has been reported to be necessary for the biogenesis of the mitochondrial ND6 mRNA, which encodes an essential subunit of mitochondrial respiratory complex I (CI, NADH:ubiquinone oxidoreductase). This study investigates the role and the mechanisms of action of FASTK in phagocytosis. Macrophages from FASTK( horizontal line / horizontal line ) mice exhibited a marked increase in nonopsonic phagocytosis of bacteria. As expected, CI activity was specifically reduced by almost 50% in those cells. To explore if decreased CI activity could underlie the phagocytic phenotype, we tested the effect of CI inhibition on phagocytosis. Indeed, treatment with CI inhibitor rotenone or short hairpin RNAs against two CI subunits (NDUFS3 and NDUFS4) resulted in a marked increase in nonopsonic phagocytosis of bacteria. Importantly, re-expression of mitoFASTK in FASTK-depleted macrophages was sufficient to rescue the phagocytic phenotype. In addition, we also report that the decrease in CI activity in FASTK( horizontal line / horizontal line ) macrophages is associated with an increase in phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) and that its inhibition using Compound C reverted the phagocytosis phenotype. Taken together, our results clearly demonstrate for the first time, to our knowledge, that mitoFASTK plays a negative regulatory role on nonopsonic phagocytosis of bacteria in macrophages through its action on CI activity. |
