Journal
MOLECULAR CELL
Volume 81, Issue 12, Pages 2520-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.04.007
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Funding
- Medical University of Vienna
- Fonds zur Forderung der wissenschaftlichen Forschung (FWF)'' as Stand-Alone Projects [P29888, P32011]
- RNA Biology Doctoral Program
- Ministry of Science and Technological Development of the Republic of Serbia [451-03-68/2020-14/200161]
- Boehringer Ingelheim Fonds PhD Fellowship
- Austrian Science Fund (FWF) [P29888, P32011] Funding Source: Austrian Science Fund (FWF)
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The tRNA ligase complex (tRNA-LC) plays a crucial role in organisms and is susceptible to oxidative inactivation. Research has shown that PYROXD1 protects tRNA-LC from oxidative inactivation through a reducing mechanism.
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.
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