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 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 Ighmbp2mediated regulation encode for components of the THO complex that link Ighmbp2 to 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 deregulated mRNA metabolism contributes to SMARD1 etiology and offers new avenues for developing alternative therapeutics to treating SMARD1.