title: Orm proteins integrate multiple signals to maintain sphingolipid homeostasis.
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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Charulatha
authors.initials: C
authors.lastname: Gururaj
authors.forename: Ross S
authors.initials: RS
authors.lastname: Federman
authors.forename: Ross
authors.initials: R
authors.lastname: Federman
authors.forename: Amy
authors.initials: A
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D025461:Feedback, Physiological; D006706:Homeostasis; D000076225:Mechanistic Target of Rapamycin Complex 2; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C548539:Orm1 protein, S cerevisiae; C548540:Orm2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; C561842:TORC1 protein complex, S cerevisiae; C406284:TSC3 protein, S cerevisiae; D014157:Transcription Factors; D051102:Serine C-Palmitoyltransferase; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; C419391:ISC1 protein, S cerevisiae; D010738:Type C Phospholipases; D002118:Calcium
keywords: Calcineurin; ER Stress; Phosphorylation; Signal Transduction; Sphingolipid; TOR