Sphingosine‐1‐phosphate controls endothelial sphingolipid homeostasis via ORMDL

Abstract

Disruption of sphingolipid homeostasis and signaling has been implicated in diabetes, cancer, cardiometabolic, and neurodegenerative disorders. Yet, mechanisms governing cellular sensing and regulation of sphingolipid homeostasis remain largely unknown. In yeast, serine palmitoyltransferase, catalyzing the first and rate‐limiting step of sphingolipid de novo biosynthesis, is negatively regulated by Orm1 and 2. Lowering sphingolipids triggers Orms phosphorylation, upregulation of serine palmitoyltransferase activity and sphingolipid de novo biosynthesis. However, mammalian orthologs ORMDLs lack the N‐terminus hosting the phosphosites. Thus, which sphingolipid(s) are sensed by the cells, and mechanisms of homeostasis remain largely unknown. Here, we identify sphingosine‐1‐phosphate (S1P) as key sphingolipid sensed by cells via S1PRs to maintain homeostasis. The increase in S1P‐S1PR signaling stabilizes ORMDLs, restraining SPT activity. Mechanistically, the hydroxylation of ORMDLs at Pro137 allows a constitutive degradation of ORMDLs via ubiquitin‐proteasome pathway, preserving SPT activity. Disrupting S1PR/ORMDL axis results in ceramide accrual, mitochondrial dysfunction, impaired signal transduction, all underlying endothelial dysfunction, early event in the onset of cardio‐ and cerebrovascular diseases. Our discovery may provide the molecular basis for therapeutic intervention restoring sphingolipid homeostasis.

Simultaneous reduction of all ORMDL proteins decreases the threshold of mast cell activation

“…Varying expression of ORMDL proteins have been shown to alter Akt kinase and nuclear factor kappa B (NF-κB) signalling pathways 18 , 19 , 24 , 25 . Levels of phosphorylated Akt kinase at serine 473 (p-Akt) following antigen activation were comparable between the various BMMC populations (Fig.…”

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

“…It remains to be tested if the degradation of human orthologues of Orm2 (ORMDL1-3) 75 , Yif1 (YIPF3), and Hmx1 (HO-1) 76,77 is conceptually similar. However, it is clear that ORMDL and HO-1 are ubiquitinated, membrane extracted and degraded by proteasomes.…”

Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis

“…A recent publication reported that ORMDL levels are regulated by S1P/S1P receptor-mediated control of ORMDL degradation in vascular endothelial cells 26 . This observation, in concert with our demonstration of a direct regulation by ceramide of SPT activity, indicates that SPT activity is homeostatically controlled at multiple levels, both direct and post-translational.…”

“…However, elevated S1P levels caused by S1P lyase deficiency have also been suggested to inhibit SPT 25 . A recent study suggests that S1P is the key sphingolipid sensed by cells via S1PR/ORMDL axis to maintain sphingolipid homeostasis by a post-translational mechanism involving accelerated ORMDL turnover 26 . Further studies are required to establish the identity of sensed sphingolipid species and the corresponding sphingolipid sensor for homeostatic regulation of SPT activity.…”