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Uncoupling of nutrient sensing and cell size control by specific defects in ceramide structure
José Ignacio Quesada-Márquez1, Ana Serrano1, María Alcaide-Gavilán1
1Department of Cell Biology, University of Seville, Seville 41012, Spain.
Biology Open
|May 7, 2026
Summary
Very-long-chain fatty acid (VLCFA) elongation to C26 is crucial for nutrient-dependent TORC2 signaling in yeast. This process regulates cell size by sensing lipid chain length, not just ceramide levels.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Ceramides are vital structural lipids with diverse acyl-chain lengths and sphingoid bases.
- The TORC2-Ypk1/2 pathway in yeast regulates plasma membrane homeostasis and cell growth.
- The specific lipid signals that modulate TORC2 activity remain incompletely understood.
Purpose of the Study:
- To investigate how ceramide structural features, particularly acyl-chain length, influence nutrient-dependent TORC2 signaling.
- To determine the role of very-long-chain fatty acid (VLCFA) elongation in regulating cell size and TORC2 activity.
- To elucidate the functional hierarchy between lipid sensing and cell size control.
Main Methods:
- Utilized Saccharomyces cerevisiae as a model organism.
- Employed genetic manipulation to disrupt VLCFA elongation (elo3Δ).
- Expressed mammalian ceramide synthases (CerS1-S4) to assess acyl-chain length specificity.
- Analyzed TORC2 signaling activity and cell size regulation under various nutrient conditions.
Main Results:
- Specific elongation of VLCFAs to C26 is essential for nutrient-dependent TORC2 downregulation.
- Disruption of VLCFA elongation leads to constitutive TORC2 hyperactivation and impaired cell size reduction.
- TORC2 nutrient-sensing is specifically tuned to acyl-chain length, with C26 being critical.
- Sphingoid-base hydroxylation is required for cell size remodeling but not for TORC2 nutrient sensing.
Conclusions:
- The length of VLCFAs, detected via a protein-mediated 'caliper' mechanism, acts as the primary sensor for TORC2 nutrient responsiveness.
- Subsequent lipid modifications, like sphingoid-base hydroxylation, govern the biophysical execution of cell size control.
- A functional hierarchy exists where lipid chain length sensing precedes the physical execution of growth regulation.
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