RNA helicase Ighmbp2 regulates THO complex to ensure cellular mRNA homeostasis
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 (DSMA1) associates with polysomes and impacts on translation of cellular mRNAs containing short, GC-rich and highly structured 5'UTRs. Absence of Ighmbp2 causes ribosome stalling at the start codon of target mRNAs, leading to their reduced translation efficiency. The main mRNA targets of Ighmbp2-mediated regulation encode for components of the THO complex that links mRNA production and nuclear export. Accordingly, failure of Ighmbp2 regulation of the THO complex causes perturbations of the cellular transcriptome and its encoded proteome. Ablation of essential THO complex subunits phenocopies these perturbations. Thus, Ighmbp2 is an upstream regulator of the THO complex that affects cellular mRNA homeostasis. Of note, Ighmbp2 dependent regulation of the THO complex is also observed in astrocytes derived from SMARD1 patients, suggesting that de-regulated mRNA metabolism contributes to SMARD1 etiology and offers new avenues for developing alternative therapeutics to treating SMARD1. Overall design: To investigate the effect of Ighmbp2 on translation, we performed RNASeq and ribosome profiling after knockdown of Ighmbp2. Additionally, to confirm ability of Ighmbp2's targets THOC to phenocopy Ighmbp2 deficiency, we performed knockdown of THOC1 or THOC2 or both and compared the transcriptome of these cells to control and Ighmbp2 knockdown conditions.