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Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion

Author

Listed:
  • Kosuke Kamemura

    (Hiroshima University)

  • Rio Kozono

    (Hiroshima University)

  • Mizuki Tando

    (Hiroshima University)

  • Misako Okumura

    (Hiroshima University
    Hiroshima University)

  • Daisuke Koga

    (Asahikawa Medical University)

  • Satoshi Kusumi

    (Kagoshima University)

  • Kanako Tamai

    (Hiroshima University)

  • Aoi Okumura

    (Hiroshima University)

  • Sayaka Sekine

    (Tohoku University)

  • Daichi Kamiyama

    (University of Georgia)

  • Takahiro Chihara

    (Hiroshima University
    Hiroshima University)

Abstract

VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.

Suggested Citation

  • Kosuke Kamemura & Rio Kozono & Mizuki Tando & Misako Okumura & Daisuke Koga & Satoshi Kusumi & Kanako Tamai & Aoi Okumura & Sayaka Sekine & Daichi Kamiyama & Takahiro Chihara, 2024. "Secretion of endoplasmic reticulum protein VAPB/ALS8 requires topological inversion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53097-5
    DOI: 10.1038/s41467-024-53097-5
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    References listed on IDEAS

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    1. Daichi Kamiyama & Sayaka Sekine & Benjamin Barsi-Rhyne & Jeffrey Hu & Baohui Chen & Luke A. Gilbert & Hiroaki Ishikawa & Manuel D. Leonetti & Wallace F. Marshall & Jonathan S. Weissman & Bo Huang, 2016. "Versatile protein tagging in cells with split fluorescent protein," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    2. Nicholas B. Woodall & Ying Yin & James U. Bowie, 2015. "Dual-topology insertion of a dual-topology membrane protein," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    3. Frederic Bard & Laetitia Casano & Arrate Mallabiabarrena & Erin Wallace & Kota Saito & Hitoshi Kitayama & Gianni Guizzunti & Yue Hu & Franz Wendler & Ramanuj DasGupta & Norbert Perrimon & Vivek Malhot, 2006. "Functional genomics reveals genes involved in protein secretion and Golgi organization," Nature, Nature, vol. 439(7076), pages 604-607, February.
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