Sphingolipid homeostasis--how do cells know when enough is enough? Implications for plant pathogen responses

Abstract Sphingolipid homeostatic regulation is important for balancing plant life and death. Plant cells finely tune sphingolipid biosynthesis to ensure sufficient levels to support growth through their basal functions as major components of endomembranes and the plasma membrane. Conversely, accumulation of sphingolipid biosynthetic intermediates, long-chain bases (LCBs) and ceramides, is associated with programmed cell death (PCD). Limiting these apoptotic intermediates is important for cell viability; while overriding homeostatic regulation permits cells to generate elevated LCBs and ceramides to respond to pathogens to elicit the hypersensitive response in plant immunity. Key to sphingolipid homeostasis is serine palmitoyltransferase (SPT), an ER-associated, multi-subunit enzyme catalyzing the first step in the biosynthesis of LCBs, the defining feature of sphingolipids. Across eukaryotes, SPT interaction with its negative regulator ORM is critical for sphingolipid biosynthesis. The recent cryo-electron microscopy structure of the Arabidopsis SPT complex indicates that ceramides bind ORMs to competitively inhibit SPT activity. This system provides a sensor for intracellular ceramide concentrations for sphingolipid homeostatic regulation. Combining the newly elucidated Arabidopsis SPT structure and mutant characterization, we present a model for the role of the two functionally divergent Arabidopsis ceramide synthase classes to produce ceramides that form repressive (trihydroxy LCB-ceramides) or non-repressive (dihydroxy LCB-ceramides) ORM interactions to influence SPT activity. We describe how sphingolipid biosynthesis is regulated by the interplay of ceramide synthases with ORM-SPT when “enough is enough” and override homeostatic suppression when “enough is not enough” to respond to environmental stimuli such as microbial pathogen attack.