Ceramides are essential structural lipids whose chemical diversity arises from variations in acyl-chain length and sphingoid-base modifications, yet how these structural features couple metabolic state to growth regulation remains unclear. In Saccharomyces cerevisiae, the target of rapamycin complex 2 (TORC2)-Ypk1/2 signaling axis coordinates plasma membrane homeostasis with cellular growth; however, the lipid-derived signals modulating this pathway are not fully defined. Here, we establish that the elongation of very long-chain fatty acids (VLCFAs), specifically to C26, is a critical determinant of the nutrient-dependent regulation of TORC2 activity. Based on a molecular caliper model for acyl-chain determination, we show that the TORC2-Ypk1 axis is specifically tuned to detect the successful completion of C26-VLCFA synthesis. Disrupting VLCFA elongation (elo3Δ) triggers constitutive TORC2 hyperactivation and a failure to reduce cell size in response to nutrient limitation. By expressing mammalian ceramide synthases (CerS1-CerS4), we demonstrate that TORC2 nutrient sensing is specifically tuned to acyl-chain length. While CerS1, CerS3, and CerS4 restore the rapid, nutrient-induced downregulation of TORC2, CerS2 expression phenocopies the elo3Δ mutant, exhibiting a total kinetic failure to inhibit TORC2 signaling upon nutrient shift. Notably, cells producing C18 ceramides (GhLag1) maintained size control despite elevated TORC2 activity, revealing that ceramide-dependent signaling intensity and the physical execution of size regulation can be uncoupled. We further demonstrate that while sphingoid-base hydroxylation is required for the execution of size remodeling, it is dispensable for nutrient sensing; sur2Δ mutants exhibited severe size defects despite maintaining statistically normal, nutrient-responsive TORC2 signaling. Overall, our findings reveal a functional hierarchy where the protein-mediated caliper measurement of VLCFA length serves as the primary sensor for TORC2 nutrient responsiveness, while subsequent lipid modifications govern the biophysical execution of cell size control.

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Journal Article

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Quesada-Márquez JI, Serrano A, Alcaide-Gavilán M, Lucena R

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