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

Michiko Shirane, Mariko Wada, Keiko Morita, Nahoki Hayashi, Reina Kunimatsu, Yuki Matsumoto, Fumiko Matsuzaki, Hirokazu Nakatsumi, Keisuke Ohta, Yasushi Tamura, Keiichi I. Nakayama

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number4576
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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