RNA helicase IGHMBP2 regulates THO complex to ensure cellular mRNA homeostasis
Archana Bairavasundaram Prusty1, Anja Hirmer1, Julieth Andrea Sierra-Delgado2
1Department of Biochemistry 1, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
Cell Reports
|February 18, 2024
Summary
The RNA helicase IGHMBP2 regulates gene translation, particularly for mRNAs with structured 5' UTRs. Its absence causes ribosome stalling and impacts the THO complex, contributing to spinal muscular atrophy with respiratory distress type 1 (SMARD1).
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- RNA helicases are crucial for RNA homeostasis and disease.
- Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a neuromuscular disorder linked to the IGHMBP2 gene.
- Dysfunctional RNA metabolism is implicated in various diseases.
Purpose of the Study:
- To investigate the role of RNA helicase IGHMBP2 in translation and its connection to SMARD1.
- To identify the mRNA targets regulated by IGHMBP2.
- To elucidate the molecular mechanisms underlying IGHMBP2 function in relation to the THO complex.
Main Methods:
- Polysome association assays to study IGHMBP2 localization.
- Analysis of mRNA translation efficiency and ribosome profiling.
- Identification of IGHMBP2 mRNA targets using transcriptomic approaches.
- Investigation of THO complex component expression and function.
Main Results:
- IGHMBP2 associates with polysomes and regulates translation of specific mRNAs with structured 5' UTRs.
- Loss of IGHMBP2 leads to ribosome stalling at start codons and reduced translation efficiency.
- Key mRNA targets of IGHMBP2 are components of the THO complex, essential for mRNA production and export.
- IGHMBP2 acts as an upstream regulator of the THO complex, and its dysregulation is observed in SMARD1 patient-derived cells.
- Perturbations in IGHMBP2-THOC regulation affect the transcriptome and proteome, mimicking THOC subunit ablation.
Conclusions:
- IGHMBP2 is a critical regulator of translation and mRNA metabolism, acting upstream of the THO complex.
- Defective IGHMBP2-THOC pathway contributes to the etiology of SMARD1.
- Understanding this pathway may reveal novel therapeutic strategies for SMARD1 and related disorders.
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