RNA helicase IGHMBP2 regulates THO complex to ensure cellular mRNA homeostasis.

Feb 19, 2024

Experts: Archana Bairavasundaram Prusty, Anja Hirmer, Julieth Andrea Sierra-Delgado, Hannes Huber, Ulf-Peter Guenther, Andreas Schlosser, Olexandr Dybkov, Ezgi Yildirim, Henning Urlaub, Kathrin C Meyer, Sibylle Jablonka, Florian Erhard, Utz Fischer

RNA helicases constitute a large protein family implicated in cellular RNA homeostasis and disease development. Here, we show that the RNA helicase IGHMBP2, linked to the neuromuscular disorder spinal muscular atrophy with respiratory distress type 1 (SMARD1), associates with polysomes and impacts translation of mRNAs containing short, GC-rich, and structured 5′ UTRs. The absence of IGHMBP2 causes ribosome stalling at the start codon of target mRNAs, leading to reduced translation efficiency. The main mRNA targets of IGHMBP2-mediated regulation encode for components of the THO complex (THOC), linking IGHMBP2 to mRNA production and nuclear export. Accordingly, failure of IGHMBP2 regulation of THOC causes perturbations of the transcriptome and its encoded proteome, and ablation of THOC subunits phenocopies these changes. Thus, IGHMBP2 is an upstream regulator of THOC. Of note, IGHMBP2-dependent regulation of THOC is also observed in astrocytes derived from patients with SMARD1 disease, suggesting that deregulated mRNA metabolism contributes to SMARD1 etiology and may enable alternative therapeutic avenues.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

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ABOUT THE EXPERTS

Archana Bairavasundaram Prusty, Anja Hirmer, Julieth Andrea Sierra-Delgado, Hannes Huber, Ulf-Peter Guenther, Andreas Schlosser, Olexandr Dybkov, Ezgi Yildirim, Henning Urlaub, Kathrin C Meyer, Sibylle Jablonka, Florian Erhard, Utz Fischer

Archana Bairavasundaram Prusty

Department of Biochemistry 1, Biocenter, University of Würzburg, 97074 Würzburg, Germany. Electronic address: archana.prusty@uni-wuerzburg.de.

Anja Hirmer

Department of Biochemistry 1, Biocenter, University of Würzburg, 97074 Würzburg, Germany.

Julieth Andrea Sierra-Delgado

Nationwide Children’s Hospital, Center for Gene Therapy, Columbus, OH 43205, USA.

Hannes Huber

Department of Biochemistry 1, Biocenter, University of Würzburg, 97074 Würzburg, Germany.

Ulf-Peter Guenther

DKMS Life Science Lab gGmbH, 01069 Dresden, Germany.

Andreas Schlosser

Rudolf-Virchow-Center, Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany.

Olexandr Dybkov

Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany.

Ezgi Yildirim

Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany.

Henning Urlaub

Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany; Department of Clinical Chemistry, University Medical Center Göttingen, 37075 Göttingen, Germany; Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany; Göttingen Center for Molecular Biosciences, University of Göttingen, Göttingen, Germany.

Kathrin C Meyer

Nationwide Children’s Hospital, Center for Gene Therapy, Columbus, OH 43205, USA; Department of Pediatrics, Ohio State University, Columbus, OH 43210, USA.

Sibylle Jablonka

Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany.

Florian Erhard

Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany; Faculty for Informatics and Data Science, University of Regensburg, 93053 Regensburg, Germany. Electronic address: florian.erhard@informatik.uni-regensburg.de.

Utz Fischer

Department of Biochemistry 1, Biocenter, University of Würzburg, 97074 Würzburg, Germany; Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), 97080 Würzburg, Germany. Electronic address: utz.fischer@uni-wuerzburg.de.