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Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation

Author

Listed:
  • Michiko Shirane

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Mariko Wada

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Keiko Morita

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Nahoki Hayashi

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Reina Kunimatsu

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Yuki Matsumoto

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Fumiko Matsuzaki

    (Medical Institute of Bioregulation, Kyushu University)

  • Hirokazu Nakatsumi

    (Graduate School of Pharmaceutical Sciences, Nagoya City University)

  • Keisuke Ohta

    (Kurume University School of Medicine)

  • Yasushi Tamura

    (Faculty of Science, Yamagata University)

  • Keiichi I. Nakayama

    (Medical Institute of Bioregulation, Kyushu University)

Abstract

Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs). The mechanism underlying lipid supply for this process and its pathophysiological relevance remains unclear, however. Here, we identify PDZD8—the mammalian ortholog of a yeast ERMES subunit—as a protein that interacts with protrudin, which is located at ER-LyLE MCSs. Protrudin and PDZD8 promote the formation of ER-LyLE MCSs, and PDZD8 shows the ability to extract various lipids from the ER. Overexpression of both protrudin and PDZD8 in HeLa cells, as well as their depletion in mouse primary neurons, impairs endosomal homeostasis by inducing the formation of abnormal large vacuoles reminiscent of those apparent in spastin- or REEP1-deficient neurons. The protrudin-PDZD8 system is also essential for the establishment of neuronal polarity. Our results suggest that protrudin and PDZD8 cooperatively promote endosome maturation by mediating ER-LyLE tethering and lipid extraction at MCSs, thereby maintaining neuronal polarity and integrity.

Suggested Citation

  • Michiko Shirane & Mariko Wada & Keiko Morita & Nahoki Hayashi & Reina Kunimatsu & Yuki Matsumoto & Fumiko Matsuzaki & Hirokazu Nakatsumi & Keisuke Ohta & Yasushi Tamura & Keiichi I. Nakayama, 2020. "Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18413-9
    DOI: 10.1038/s41467-020-18413-9
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    Cited by:

    1. Yunyun Wang & Zhenni Li & Xinyu Wang & Ziyuan Zhao & Li Jiao & Ruming Liu & Keying Wang & Rui Ma & Yang Yang & Guo Chen & Yong Wang & Xin Bian, 2023. "Insights into membrane association of the SMP domain of extended synaptotagmin," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Darshini Jeyasimman & Bilge Ercan & Dennis Dharmawan & Tomoki Naito & Jingbo Sun & Yasunori Saheki, 2021. "PDZD-8 and TEX-2 regulate endosomal PI(4,5)P2 homeostasis via lipid transport to promote embryogenesis in C. elegans," Nature Communications, Nature, vol. 12(1), pages 1-21, December.

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