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Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway

Author

Listed:
  • Ruud H. Wijdeven

    (The Netherlands Cancer Institute)

  • Hans Janssen

    (The Netherlands Cancer Institute)

  • Leila Nahidiazar

    (The Netherlands Cancer Institute)

  • Lennert Janssen

    (The Netherlands Cancer Institute
    Leiden University Medical Center)

  • Kees Jalink

    (The Netherlands Cancer Institute)

  • Ilana Berlin

    (The Netherlands Cancer Institute
    Leiden University Medical Center)

  • Jacques Neefjes

    (The Netherlands Cancer Institute
    Leiden University Medical Center)

Abstract

Autophagy is the main homeostatic pathway guiding cytosolic materials for degradation by the lysosome. Maturation of autophagosomes requires their transport towards the perinuclear region of the cell, with key factors underlying both processes still poorly understood. Here we show that transport and positioning of late autophagosomes depends on cholesterol by way of the cholesterol-sensing Rab7 effector ORP1L. ORP1L localizes to late autophagosomes and—under low-cholesterol conditions—contacts the ER protein VAP-A, forming ER-autophagosome contact sites, which prevent minus-end transport by the Rab7–RILP–dynein complex. ORP1L-mediated contact sites also inhibit localization of PLEKHM1 to Rab7. PLEKHM1, together with RILP, then recruits the homotypic fusion and vacuole protein-sorting (HOPS) complex for fusion of autophagosomes with late endosomes and lysosomes. Thus, ORP1L, via its liganding by lipids and the formation of contacts between autophagic vacuoles and the ER, governs the last steps in autophagy that lead to the lysosomal degradation of cytosolic material.

Suggested Citation

  • Ruud H. Wijdeven & Hans Janssen & Leila Nahidiazar & Lennert Janssen & Kees Jalink & Ilana Berlin & Jacques Neefjes, 2016. "Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11808
    DOI: 10.1038/ncomms11808
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    Cited by:

    1. Tong Zhang & Yifan Li & Chengyang Li & Jingze Zang & Erlin Gao & Johan T. Kroon & Xiaolu Qu & Patrick J. Hussey & Pengwei Wang, 2023. "Exo84c interacts with VAP27 to regulate exocytotic compartment degradation and stigma senescence," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Lifeng Chen & Jingjing Zhang & Weibin Xu & Jiayi Chen & Yujun Tang & Si Xiong & Yaolan Li & Hong Zhang & Manmei Li & Zhong Liu, 2024. "Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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