Deletion of sulfate transporter SUL1 extends yeast replicative lifespan via reduced PKA signaling instead of decreased sulfate uptake

The regulation of cellular metabolism and growth in response to nutrient availability is essential for cell survival and can significantly impact lifespan. Central to the regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this work, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate inS. cerevisiae, as a key gene for regulating lifespan. We performed a systematic analysis to delineate the downstream mechanism underlying the lifespan extension by SUL1 deletion. Surprisingly, we found that the lifespan extending effect of SUL1 deletion is not caused by decreased sulfate transport. SUL1 deletion mutant exhibited decreased PKA signaling, resulting in a range of downstream effects, including increased stress-protective trehalose and glycogen, increased nuclear translocation of MSN2 and elevated expression of general stress response genes, enhanced autophagy, and reduced expression of amino acid biosynthetic and ribosomal genes. We show that the observed increase in lifespan is dependent on MSN2 and autophagy pathways. Our findings exemplify the influence of nutrient signaling, rather than the nutrient itself, on lifespan regulation and further substantiate the pivotal role of the PKA pathway in this process.