The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response

Igor Asanović, Emilia Strandback, Alena Kroupova, Djurdja Pasajlic, Anton Meinhart, Pai Tsung-Pin, Nemanja Djokovic, Dorothea Anrather, Thomas Schuetz, Marcin Józef Suskiewicz, Sirelin Sillamaa, Thomas Köcher, Rebecca Beveridge, Katarina Nikolic, Alexander Schleiffer, Martin Jinek, Markus Hartl, Tim Clausen, Josef Penninger, Peter MacherouxStefan Weitzer*, Javier Martinez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2520-2532.e16
Number of pages13
JournalMolecular Cell
Volume81
Issue number12
DOIs
Publication statusPublished - 17 Jun 2021

Keywords

  • copper
  • metalloenzyme
  • myopathy
  • NADH
  • NADPH
  • oxidative stress
  • oxidoreductase
  • pre-tRNA splicing
  • PYROXD1
  • RtcB
  • tRNA ligase complex
  • UPR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fields of Expertise

  • Human- & Biotechnology

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