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 and Keiichi I. Nakayama ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18413-9

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