Orm family proteins mediate sphingolipid homeostasis

By David K. Breslow, Sean R. Collins, Bernd Bodenmiller, R. Aebersold, K. Simons, Andrej Shevchenko, Christer S. Ejsing, Jonathan S. Weissman. Nature, 2010

603 citations recorded by the source corpus.

Despite the essential roles of sphingolipids both as structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM genes (known as ORMDL genes in humans)—a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach in Saccharomyces cerevisiae, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2a3147a65f9f492582fb983a387aa8eda953e00e

How researchers see this paper

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In Cell Biology

1. Shiyu Wang
2. R. Kaufman
3. Michael N. Hall
4. T. Balla
5. R. Loewith
6. J. Malhotra
7. G. Hotamışlıgil
8. D. Ron

In Molecular Biology

1. Michael N. Hall
2. R. Loewith
3. Shiyu Wang
4. T. Balla
5. R. Kaufman
6. David M. Sabatini
7. K. Guan
8. G. Hotamışlıgil

In Physiology

1. Michael N. Hall
2. T. Balla
3. R. Kaufman
4. R. Loewith

Citations in the corpus

• A Large-Scale, Consortium-Based Genomewide Association Study of Asthma (2010, neutral): “ALSPAC United Kingdom 607 607 (57) — 609 609 (51) — B58C United Kingdom 445 213 (56) 232 (38) 420 200 (44) 220 (50) BAMSE Sweden 239 239 (63) — 246 246 (48) — BUSSELTON Australia 398 188 (51) 210 (33) 809 390 (45) 419 (41) CAPPS and SAGE Canada 88 88 (66) — 182 182 (51) — ECRHS Multiple countries 66”
• Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control (2011, background): “The conserved Orm proteins, identified as a potential risk factor for childhood asthma, form a complex that negatively regulates the first and rate-limiting step in sphingolipid biosynthesis (Breslow et al. 2010; Han et al. 2010).”
• The impact of the unfolded protein response on human disease (2012, background): “(2) Risk of childhood asthma Hjelmqvist et al., 2002; Breslow et al., 2010; McGovern et al., 2010”
• Phosphoinositides: tiny lipids with giant impact on cell regulation. (2013, background): “This also suggests a link between sphingolipid status and PtdIns4P regulation (178).”