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Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair

Author

Listed:
  • Patrick Niekamp

    (University of Osnabrück)

  • Felix Scharte

    (University of Osnabrück)

  • Tolulope Sokoya

    (University of Osnabrück)

  • Laura Vittadello

    (University of Osnabrück)

  • Yeongho Kim

    (Yale School of Medicine)

  • Yongqiang Deng

    (Yale School of Medicine)

  • Elisabeth Südhoff

    (University of Osnabrück)

  • Angelika Hilderink

    (University of Osnabrück)

  • Mirco Imlau

    (University of Osnabrück)

  • Christopher J. Clarke

    (Stony Brook University)

  • Michael Hensel

    (University of Osnabrück)

  • Christopher G. Burd

    (Yale School of Medicine)

  • Joost C. M. Holthuis

    (University of Osnabrück)

Abstract

Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger a rapid calcium-activated scrambling and cytosolic exposure of sphingomyelin. Subsequent metabolic conversion of sphingomyelin by neutral sphingomyelinases on the cytosolic surface of injured lysosomes promotes their repair, also when ESCRT function is compromised. Conversely, blocking turnover of cytosolic sphingomyelin renders cells more sensitive to lysosome-damaging drugs. Our data indicate that calcium-activated scramblases, sphingomyelin, and neutral sphingomyelinases are core components of a previously unrecognized membrane restoration pathway by which cells preserve the functional integrity of lysosomes.

Suggested Citation

  • Patrick Niekamp & Felix Scharte & Tolulope Sokoya & Laura Vittadello & Yeongho Kim & Yongqiang Deng & Elisabeth Südhoff & Angelika Hilderink & Mirco Imlau & Christopher J. Clarke & Michael Hensel & Ch, 2022. "Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29481-4
    DOI: 10.1038/s41467-022-29481-4
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    References listed on IDEAS

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    1. Luana L. Scheffer & Sen Chandra Sreetama & Nimisha Sharma & Sushma Medikayala & Kristy J. Brown & Aurelia Defour & Jyoti K. Jaiswal, 2014. "Mechanism of Ca2+-triggered ESCRT assembly and regulation of cell membrane repair," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    2. Jun Suzuki & Masato Umeda & Peter J. Sims & Shigekazu Nagata, 2010. "Calcium-dependent phospholipid scrambling by TMEM16F," Nature, Nature, vol. 468(7325), pages 834-838, December.
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