HSP-1/HSPA8 directs selective translation towards longevity or immunity

Abstract As organisms age there is a progressive decline in protein homeostasis, yet how mRNAs are selectively translated during aging remains poorly understood. Since cells do not have limitless energy, choices must be made as to which set of proteins are translated at the expense of other proteins which might be less essential. Here, we identify that the Hsp70 chaperone protein HSP-1/HSPA8 binds to the ribosome and helps to direct selective translation in Caenorhabditis elegans. We find that intestine-specific depletion of HSP-1 accelerates ageing and abolishes the longevity conferred by reduced translation. Intestinal translatome profiling revealed that HSP-1 depletion decreases ribosome occupancy on lysosomal transcripts while increasing occupancy on immune- and stress-response mRNAs, including MAPK pathway components. This translational shift activates the p38 TIR-1-MAPK innate immune pathway and impairs autophagy through impaired lysosomal acidification. Similarly, depletion of the human orthologue HSPA8 increases p38 phosphorylation and decreases lysosomal acidification, suggesting that this could be a conserved regulator of selective translation. Although this response enhances resistance to bacterial infection in C. elegans, it comes at the cost of shortened lifespan, revealing a trade-off between host defense and longevity. While decreased lifespan is dependent on autophagy pathways, increased resistance to infection depends on the p38-MAPK pathway. Together, these findings identify HSP-1 as a ribosome-associated chaperone that couples selective translation to autophagy, innate immunity, and ageing.