5' UTR-mediated retention of eIF3 on 80S ribosomes promotes co-translational folding of ER membrane proteins

Han, B.; Zhang, S.; Duan, H.; Zhang, Y.; Yu, B.; Lin, W.; Cheng, Y.; Wolf, D. A.

doi:10.1101/2025.01.19.633751

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bioRxiv · 10.1101/2025.01.19.633751

5' UTR-mediated retention of eIF3 on 80S ribosomes promotes co-translational folding of ER membrane proteins

Han, B.·Zhang, S.·Duan, H.·Zhang, Y.·Yu, B.·Lin, W.·Cheng, Y.·Wolf, D. A.

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Abstract

Co-translational folding of nascent polypeptides is essential for protein function and cellular homeostasis. Ribosome-associated chaperones assist in this process, but coordination between their recruitment and translation initiation remains poorly understood. We report here that specific binding sites for eukaryotic translation initiation factor eIF3 within the 5 untranslated regions (5UTRs) of mRNAs promote its retention on 80S ribosomes during the synthesis of select endoplasmic reticulum (ER) membrane proteins. Disruption of these eIF3 binding sites leads to misfolding and sequestration of newly synthesized membrane proteins into ER whorls. Sequestration into ER whorls is exacerbated by HSP70 inhibition but can be rescued by overexpressing HSPA8 and HSPA1. Cross-linking assays reveal that 5UTR binding sites stabilize eIF3-80S interactions during early elongation, facilitating recruitment of HSPA8 to ribosomes. These findings indicate that genetic instructions within 5UTRs direct eIF3-mediated chaperone recruitment, ensuring proper co-translational folding of ER membrane proteins.

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Han, B., Zhang, S., Duan, H., Zhang, Y., Yu, B., Lin, W., Cheng, Y., Wolf, D. A.. 2025-01-19. 5' UTR-mediated retention of eIF3 on 80S ribosomes promotes co-translational folding of ER membrane proteins. https://doi.org/10.1101/2025.01.19.633751

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