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HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels

Author

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  • Petter Holland

    (Institute of Basic Medical Sciences, University of Oslo)

  • Helene Knævelsrud

    (Institute of Basic Medical Sciences, University of Oslo)

  • Kristiane Søreng

    (Institute of Basic Medical Sciences, University of Oslo)

  • Benan J. Mathai

    (Institute of Basic Medical Sciences, University of Oslo)

  • Alf Håkon Lystad

    (Institute of Basic Medical Sciences, University of Oslo)

  • Serhiy Pankiv

    (Institute of Basic Medical Sciences, University of Oslo)

  • Gunnveig T. Bjørndal

    (Institute of Basic Medical Sciences, University of Oslo)

  • Sebastian W. Schultz

    (Centre for Cancer Biomedicine, Institute for Cancer Research, Oslo University Hospital)

  • Viola H. Lobert

    (Centre for Cancer Biomedicine, Institute for Cancer Research, Oslo University Hospital)

  • Robin B. Chan

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center)

  • Bowen Zhou

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center)

  • Knut Liestøl

    (Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo)

  • Sven R. Carlsson
  • Thomas J. Melia

    (Yale University School of Medicine)

  • Gilbert Di Paolo

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center)

  • Anne Simonsen

    (Institute of Basic Medical Sciences, University of Oslo)

Abstract

A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1- and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids.

Suggested Citation

  • Petter Holland & Helene Knævelsrud & Kristiane Søreng & Benan J. Mathai & Alf Håkon Lystad & Serhiy Pankiv & Gunnveig T. Bjørndal & Sebastian W. Schultz & Viola H. Lobert & Robin B. Chan & Bowen Zhou , 2016. "HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13889
    DOI: 10.1038/ncomms13889
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    Cited by:

    1. Michael J. Munson & Benan J. Mathai & Matthew Yoke Wui Ng & Laura Trachsel-Moncho & Laura R. Ballina & Sebastian W. Schultz & Yahyah Aman & Alf H. Lystad & Sakshi Singh & Sachin Singh & Jørgen Wesche , 2021. "GAK and PRKCD are positive regulators of PRKN-independent mitophagy," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    2. Keisuke Tabata & Vibhu Prasad & David Paul & Ji-Young Lee & Minh-Tu Pham & Woan-Ing Twu & Christopher J. Neufeldt & Mirko Cortese & Berati Cerikan & Yannick Stahl & Sebastian Joecks & Cong Si Tran & C, 2021. "Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Paula P. Coelho & Geoffrey G. Hesketh & Annika Pedersen & Elena Kuzmin & Anne-Marie N. Fortier & Emily S. Bell & Colin D. H. Ratcliffe & Anne-Claude Gingras & Morag Park, 2022. "Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Leslie A. Rowland & Adilson Guilherme & Felipe Henriques & Chloe DiMarzio & Sean Munroe & Nicole Wetoska & Mark Kelly & Keith Reddig & Gregory Hendricks & Meixia Pan & Xianlin Han & Olga R. Ilkayeva &, 2023. "De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Morgane Mabire & Pushpa Hegde & Adel Hammoutene & Jinghong Wan & Charles Caër & Rola Al Sayegh & Mathilde Cadoux & Manon Allaire & Emmanuel Weiss & Tristan Thibault-Sogorb & Olivier Lantz & Michèle Go, 2023. "MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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