Rpl12 paralog dependent TOR-signaling controls the expression of ribosome preservation factor Stm1

ABSTRACT Ribosomes are increasingly recognized as heterogeneous regulators of gene expression, yet how ribosomal protein paralogs interface with nutrient signaling remains poorly understood. In Saccharomyces cerevisiae , ribosomal protein gene expression is governed by duplicated gene pairs, many of which exhibit functional divergence despite high sequence identity. A central regulator of ribosome biogenesis and translational control is the Target of Rapamycin (TOR) pathway, which integrates nutrient signals to modulate growth, stress adaptation, and lifespan. Target of Rapamycin Complex 1 (TORC1) influences ribosome activity by phosphorylating ribosomal protein S6 (Rps6), a modification that links nutrient availability to translational output. Here, we investigated the functional divergence of the Rpl12 ribosomal stalk protein paralogs RPL12a and RPL12b and found that rpl12bΔ produces phenotypes consistent with reduced TOR activity, including decreased Rps6 phosphorylation, G2/M cell-cycle accumulation, and significant extension of chronological lifespan as compared to rpl12aΔ and wildtype strain. Multi-omics analyses further indicate translational and metabolic reprogramming consistent with activation of a stress-adaptive program associated with Gcn4. Importantly, loss of RPL12b also reduces levels of the ribosome preservation factor Stm1, a TORC1-regulated protein required for stabilization of 80S ribosomes under stress. This finding links ribosomal stalk composition to ribosome stability and nutrient-responsive signaling. Together, our results demonstrate that ribosomal paralog specialization provides an additional regulatory layer connecting translation, TOR signaling, and cellular longevity.