Efficient translation of chaperones by eIF5A safeguards proteostasis under heat stress

Abstract

The increase in global temperature poses a major threat to cells and organisms because it disrupts cellular proteostasis. We discovered that the evolutionarily conserved and essential translation elongation factor eIF5A is necessary for a rapid response to heat-stress in yeast cells. Lack of eIF5A results in ribosome stalling on heat-stress-induced mRNAs, reducing the synthesis of chaperones, primarily impacting those that undergo robust synthesis via high codon optimality, such as Hsp70 Ssa1 and Hsp12 chaperones. This new eIF5A role in translation appears to be direct, as eIF5A binds preferentially to induced mRNAs with high codon optimality and its polysome association increases under heat-shock. Low levels of Hsp70 in eIF5A mutants delay Hsf1 feedback inhibition during stress adaptation and cause the accumulation of protein aggregates, resulting in low cellular viability to heat-stress. Overall, our results show that eIF5A is crucial for heat-stress resistance by facilitating rapid and efficient translation of high codon-optimal chaperones. Therefore, eIF5A emerges as a key regulator of cellular proteostasis, providing a novel perspective on its significant involvement in neurodegenerative diseases and aging.