Regulation of sphingolipid synthesis via Orm1 and Orm2 in yeast

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Abstract
Sphingolipids are crucial components of membranes, and sphingolipid metabolites serve as signaling molecules. Yeast Orm1 and Orm2 belong to a conserved family of ER membrane proteins that regulate serine palmitoyltransferase, which catalyzes the first and rate-limiting step in sphingolipid synthesis. We now show that sphingolipid synthesis through Orm1 is a target of TOR signaling, which regulates cell growth in response to nutritional signals. Orm1 phosphorylation is dependent on the Tap42–phosphatase complex, which acts downstream of TOR protein kinase complex 1. In temperature-sensitive tap42-11 cells, impaired Orm1 phosphorylation occurs concomitantly with reduced sphingolipid synthesis. A second mechanism for regulating sphingolipid synthesis is through control of Orm2 protein level. The Orm2 protein level responds to ER stress conditions, increasing when cells are treated with tunicamycin or DTT, agents that induce the unfolded protein response (UPR). The sphingolipid intermediates (long chain base and ceramide) are decreased when ORM2 is overexpressed, suggesting that sphingolipid synthesis is repressed under ER stress conditions. Finally, in the absence of the Orms, the UPR is constitutively activated. Lipid dysregulation in the absence of the Orms might signal to the ER from the plasma membrane because UPR activation is dependent on a cell surface sensor and the mitogen-activated protein kinase (MAPK) cell wall integrity pathway. Thus, sphingolipid synthesis and the UPR are coordinately regulated.

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