RNA helicase Ighmbp2 regulates THO complex to ensure cellular mRNA homeostasis

Published: 18 January 2024| Version 4 | DOI: 10.17632/cnympvsrgt.4
Contributors:
,
,
,
,
,
, Olexandr Dybkov, Ezgi Yildirim,
, Kathrin Meyer, Sibylle Jablonka,
,

Description

Abstract 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 SMARD1 associates with polysomes and impacts translation of mRNAs containing short, GC-rich and structured 5’UTRs. 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. File conent: Raw full blots as TIFF files. R-script for pSILAC analysis.

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Institutions

Nationwide Children's Hospital, Ohio State University, Universitat Regensburg, Georg-August-Universitat Gottingen, Julius-Maximilians-Universitat Wurzburg, Helmholtz-Institut fur RNA-basierte Infektionsforschung

Categories

Neurological Disease Mechanisms, Messenger RNA, Translation (Protein Synthesis), Helicase

Funding

Deutsche Forschungsgemeinschaft

Fi 573/15-2

National Institutes of Health

P50AR070604

Deutsche Forschungsgemeinschaft

JA 1823/5-1

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