| First Author | Asanović I | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 12 | Pages | 2520-2532.e16 |
| PubMed ID | 33930333 | Mgi Jnum | J:314428 |
| Mgi Id | MGI:6718914 | Doi | 10.1016/j.molcel.2021.04.007 |
| Citation | Asanovic I, et al. (2021) The oxidoreductase PYROXD1 uses NAD(P)(+) as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response. Mol Cell 81(12):2520-2532.e16 |
| abstractText | The tRNA ligase complex (tRNA-LC) splices precursor tRNAs (pre-tRNA), and Xbp1-mRNA during the unfolded protein response (UPR). In aerobic conditions, a cysteine residue bound to two metal ions in its ancient, catalytic subunit RTCB could make the tRNA-LC susceptible to oxidative inactivation. Here, we confirm this hypothesis and reveal a co-evolutionary association between the tRNA-LC and PYROXD1, a conserved and essential oxidoreductase. We reveal that PYROXD1 preserves the activity of the mammalian tRNA-LC in pre-tRNA splicing and UPR. PYROXD1 binds the tRNA-LC in the presence of NAD(P)H and converts RTCB-bound NAD(P)H into NAD(P)(+), a typical oxidative co-enzyme. However, NAD(P)(+) here acts as an antioxidant and protects the tRNA-LC from oxidative inactivation, which is dependent on copper ions. Genetic variants of PYROXD1 that cause human myopathies only partially support tRNA-LC activity. Thus, we establish the tRNA-LC as an oxidation-sensitive metalloenzyme, safeguarded by the flavoprotein PYROXD1 through an unexpected redox mechanism. |
