AI Article Synopsis
- RNA helicases are important for maintaining RNA levels in cells and are linked to diseases, such as SMARD1, which is associated with the IGHMBP2 protein.* -
- IGHMBP2 helps in translating specific mRNAs by preventing ribosome stalling, which is crucial for synthesizing proteins involved in the THO complex, important for mRNA production and export.* -
- Problems with IGHMBP2 regulation can disrupt cellular processes and may play a role in the development of SMARD1, highlighting potential targets for new treatments.*
Article 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 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.
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| http://dx.doi.org/10.1016/j.celrep.2024.113802 | DOI Listing |
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