Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide adenine dinucleotide cofactors

Elizabeth T. Abshire, Kelsey L. Hughes, Rucheng Diao, Sarah Pearce, Shreekara Gopalakrishna, Raymond C. Trievel, Joanna Rorbach, Peter L. Freddolino, Aaron C. Goldstrohm

Research output: Contribution to journalArticlepeer-review

Abstract

Nocturnin (NOCT) is a eukaryotic enzyme that belongs to a superfamily of exoribonucleases, endonucleases, and phosphatases. In this study, we analyze the expression, processing, localization, and cellular functions of human NOCT. We find that NOCT protein is differentially expressed and processed in a cell and tissue type-specific manner to control its localization to the cytoplasm or mitochondrial exterior or interior. The N terminus of NOCT is necessary and sufficient to confer import and processing in the mitochondria. We measured the impact of cytoplasmic NOCT on the transcriptome and observed that it affects mRNA levels of hundreds of genes that are significantly enriched in osteoblast, neuronal, and mitochondrial functions. Recent biochemical data indicate that NOCT dephosphorylates NADP(H) metabolites, and thus we measured the effect of NOCT on these cofactors in cells. We find that NOCT increases NAD(H) and decreases NADP(H) levels in a manner dependent on its intracellular localization. Collectively, our data indicate that NOCT can regulate levels of both mRNAs and NADP(H) cofactors in a manner specified by its location in cells.

Original languageEnglish (US)
Pages (from-to)15112-15133
Number of pages22
JournalJournal of Biological Chemistry
Volume295
Issue number44
DOIs
StatePublished - Oct 30 2020

Bibliographical note

Funding Information:
Funding and additional information—This research was supported

Funding Information:
by funding from the Max Planck Institute, Karolinska Institutet, Marie Sklodowska Curie Actions International Career Grant 2015-00579, and Knut and Alice Wallenberg Foundation Grant WAF

Funding Information:
We thank the members of the Goldstrohm, Freddolino, Trievel, and Rorbach laboratories for helpful suggestions and advice during the course of these studies. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. This research was supported by funding from the Max Planck Institute, Karolinska Institutet, Marie Sklodowska Curie Actions International Career Grant 2015-00579, and Knut and Alice Wallenberg Foundation Grant WAF

Funding Information:
Acknowledgments—We thank the members of the Goldstrohm, Freddolino, Trievel, and Rorbach laboratories for helpful suggestions and advice during the course of these studies. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Publisher Copyright:
© 2020 Abshire et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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