Proteomics

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The oxidoreductase PYROXD1 links human myopathies with pre-tRNA splicing and the unfolded protein response.

ABSTRACT: PYROXD1 is a largely unstudied essential flavoprotein, whose variants were recently reported to cause myopathies in humans. Here, we report the first biochemical and structural characterization of PYROXD1 and uncover its function as a protector of the tRNA ligase complex from oxidative inactivation. The tRNA ligase complex is essential for the biogenesis of several tRNAs and for the unfolded protein response in humans, and loses activity in cells depleted of PYROXD1. Our mass spectrometry analysis of immunoprecipitates of FLAG-PYROXD1 revealed the tRNA ligase complex as the main interactor of PYROXD1 in presence of nicotinamide adenine dinucleotides, NAD(P)(H). Upon binding to the tRNA ligase complex loaded with NAD(P)H, which sensitizes it to oxidative inactivation, PYROXD1 locally converts the dinucleotide to the protective, oxidized form, NAD(P)+. This function is impaired in disease-causing variants N155S and Q372H, thus establishing the tRNA ligase complex as a potential key player in PYROXD1-related myopathies.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hek-293 Cell

SUBMITTER: Dorothea Anrather  

LAB HEAD: Javier Martinez

PROVIDER: PXD018831 | Pride | 2021-06-24

REPOSITORIES: Pride

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20190506_QExHFX3_RSLC2_Asanovic_Martinez_MFPL_IPs_s1_10p.raw Raw
20190506_QExHFX3_RSLC2_Asanovic_Martinez_MFPL_IPs_s2_10p.raw Raw
20190506_QExHFX3_RSLC2_Asanovic_Martinez_MFPL_IPs_s5_10p.raw Raw
20190506_QExHFX3_RSLC2_Asanovic_Martinez_MFPL_IPs_s6_10p.raw Raw
20190823_Pyroxd1_PD_complete_proteinGroups_LIMMA_t-test_final.xlsx Xlsx
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Publications

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 mam  ...[more]

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