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Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Author

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  • Mouhannad Malek

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP))

  • Anna M. Wawrzyniak

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP))

  • Peter Koch

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP))

  • Christian Lüchtenborg

    (Heidelberg University)

  • Manuel Hessenberger

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP))

  • Timo Sachsenheimer

    (Heidelberg University)

  • Wonyul Jang

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP))

  • Britta Brügger

    (Heidelberg University)

  • Volker Haucke

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
    Freie Universität Berlin)

Abstract

Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites.

Suggested Citation

  • Mouhannad Malek & Anna M. Wawrzyniak & Peter Koch & Christian Lüchtenborg & Manuel Hessenberger & Timo Sachsenheimer & Wonyul Jang & Britta Brügger & Volker Haucke, 2021. "Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22882-x
    DOI: 10.1038/s41467-021-22882-x
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    Cited by:

    1. Maria Casas & Karl D. Murray & Keiko Hino & Nicholas C. Vierra & Sergi Simó & James S. Trimmer & Rose E. Dixon & Eamonn J. Dickson, 2023. "NPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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