Journal
EMBO JOURNAL
Volume 36, Issue 12, Pages 1736-1754Publisher
WILEY
DOI: 10.15252/embj.201696048
Keywords
ceramide; lipid territories; lipid-transfer protein; membrane contact sites; PtdIns(4)P
Categories
Funding
- AIRC [MFAG 10585]
- Italian Ministry of Health [GR-2011-02352256]
- MIUR [PON_00862]
- FIRC [15111]
- FFC [Italian Cystic Fibrosis Research Foundation FFC] [2 2014]
- MIUR [COSM Progetto Interomics]
- AIRC [Italian Association for Cancer Research] [IG 15767]
- MIUR Project FaReBio di Qualita
- PON Projects [01/00117, 01-00862]
- PNR-CNR Aging Program
- Progetto Bandiera Epigen
- NIH [5P01CA097132-12-NCI]
- Academy of Finland [282192, 284667, 307415]
- Swiss National Science Foundation
- NCCR Chemical Biology
- Ministerio de Economia y Competitividad, Centro de Excelencia Severo Ochoa [SEV-2012-0208]
- Ministerio de Economia y Competitividad's Plan Nacional [BFU2013-44188-P]
- Academy of Finland (AKA) [284667, 284667] Funding Source: Academy of Finland (AKA)
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Sphingolipids are membrane lipids globally required for eukaryotic life. The sphingolipid content varies among endomembranes with pre- and post-Golgi compartments being poor and rich in sphingolipids, respectively. Due to this different sphingolipid content, pre- and post-Golgi membranes serve different cellular functions. The basis for maintaining distinct subcellular sphingolipid levels in the presence of membrane trafficking and metabolic fluxes is only partially understood. Here, we describe a homeostatic regulatory circuit that controls sphingolipid levels at the trans-Golgi network (TGN). Specifically, we show that sphingomyelin production at the TGN triggers a signalling pathway leading to PtdIns(4)P dephosphorylation. Since PtdIns(4) P is required for cholesterol and sphingolipid transport to the trans-Golgi network, PtdIns(4)P consumption interrupts this transport in response to excessive sphingomyelin production. Based on this evidence, we envisage a model where this homeostatic circuit maintains a constant lipid composition in the trans-Golgi network and post-Golgi compartments, thus counteracting fluctuations in the sphingolipid biosynthetic flow.
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