Sphingosine-1-phosphate controls endothelial sphingolipid homeostasis via ORMDL.

TitleSphingosine-1-phosphate controls endothelial sphingolipid homeostasis via ORMDL.
Publication TypeJournal Article
Year of Publication2023
AuthorsSasset L, Chowdhury KH, Manzo OL, Rubinelli L, Konrad C, J Maschek A, Manfredi G, Holland WL, Di Lorenzo A
JournalEMBO Rep
Date Published2023 Jan 09
KeywordsAnimals, Homeostasis, Humans, Mammals, Membrane Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Serine C-Palmitoyltransferase, Sphingolipids

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.

Alternate JournalEMBO Rep
PubMed ID36408842
PubMed Central IDPMC9827560
Grant ListR01 HL126913 / HL / NHLBI NIH HHS / United States
R01 HL152195 / HL / NHLBI NIH HHS / United States
R35 NS122209 / NS / NINDS NIH HHS / United States
Related Faculty: 
Annarita Di Lorenzo, Ph.D.

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