hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response

Abstract

Abstract Cells adapt to metabolic stress by orchestrating gene expression to mitigate cellular damage, sustain homeostasis, and promote survival. Within this framework, translational control provides a rapid and efficient layer of regulation. Non-coding RNAs have recently emerged as effective modulators of translation, partly by targeting the ribosome. The contribution of ribosome-associated non-coding RNAs (rancRNAs) to translation regulation, however, remains largely unexplored in human cells. Here, we identified the human Y3 (hY3) RNA as a rancRNA that inhibits protein synthesis and attenuates cellular metabolism. hY3 function was particularly critical under nutrient deprivation, where it promoted adaptive stress responses. In this context, depletion of hY3 disrupted the delicate balance between survival and apoptosis by reducing the expression of pro-survival factors and impairing the activation of the integrated stress response (ISR). Loss of hY3 reduced starvation-dependent phosphorylation of eukaryotic translation initiation factor 2α, thereby attenuating ISR signalling, which results in non-physiologically elevated global translation rates during nutrient deprivation. Together, our findings establish hY3 as a ribosome-bound regulator of translation and stress responses, positioning it as a determinant of cell fate under metabolic stress.