Abstract
Sphingolipids are structural components of membranes, and sphingolipid metabolites serve as signaling molecules. The first and rate-limiting step in sphingolipid synthesis is catalyzed by serine palmitoyltransferase (SPT). The recently discovered SPT-associated proteins, Orm1 and Orm2, are critical regulators of sphingolipids. Orm protein phosphorylation mediating feedback regulation of SPT activity occurs in response to multiple sphingolipid intermediates, including long chain base and complex sphingolipids. Both branches of the TOR signaling network, TORC1 and TORC2, participate in regulating sphingolipid synthesis via Orm phosphorylation in response to sphingolipid intermediates as well as nutritional conditions. Moreover, sphingolipid synthesis is regulated in response to endoplasmic reticulum (ER) stress by activation of a calcium- and calcineurin-dependent pathway via transcriptional induction of ORM2. Conversely, the calcium- and calcineurin-dependent pathway signals ER stress response upon lipid dysregulation in the absence of the Orm proteins to restore ER homeostasis.
Highlights
Orm proteins are key regulators of sphingolipid synthesis
We show that sphingolipid synthesis is regulated via Orm phosphorylation by a feedback mechanism that responds to multiple sphingolipid intermediates, including long chain base as well as complex sphingolipid(s)
A Calcium-dependent Signaling Pathway Regulates Orm2 Protein Levels—In response to protein misfolding in the endoplasmic reticulum (ER) induced by tunicamycin or DTT, Orm2 protein abundance increased, as shown by Western blot of TAP-tagged Orm2 (Fig. 1A) [3, 6]. (Orm2-TAP is functional because it retains its association with serine palmitoyltransferase (SPT) components [3].) The unfolded protein response (UPR), the major transcriptional response to protein misfolding in the ER, requires the sensor Ire1 to activate the transcription factor Hac1 [17]
Summary
Orm proteins are key regulators of sphingolipid synthesis. Results: Orm and Orm are phosphorylated by TORC1 and TORC2; Orm is transcriptionally regulated by a calcium- and calcineurin-dependent pathway. Orm protein phosphorylation mediating feedback regulation of SPT activity occurs in response to multiple sphingolipid intermediates, including long chain base and complex sphingolipids. Both branches of the TOR signaling network, TORC1 and TORC2, participate in regulating sphingolipid synthesis via Orm phosphorylation in response to sphingolipid intermediates as well as nutritional conditions. Sphingolipid synthesis is regulated in response to endoplasmic reticulum (ER) stress by activation of a calcium- and calcineurin-dependent pathway via transcriptional induction of ORM2. The calcium- and calcineurin-dependent pathway signals ER stress response upon lipid dysregulation in the absence of the Orm proteins to restore ER homeostasis. In response to ER stress, sphingolipid synthesis is modulated by a calcium- and calcineurin-dependent pathway that regulates Orm protein level. Lipid dysregulation in the absence of the Orm proteins activates calcium- and calcineurin-dependent signaling to ameliorate ER stress
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