RRC ID 64103
Author Shirane M, Wada M, Morita K, Hayashi N, Kunimatsu R, Matsumoto Y, Matsuzaki F, Nakatsumi H, Ohta K, Tamura Y, Nakayama KI.
Title Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation.
Journal Nat Commun
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.
Volume 11(1)
Pages 4576
Published 2020-9-11
DOI 10.1038/s41467-020-18413-9
PII 10.1038/s41467-020-18413-9
PMID 32917905
PMC PMC7486383
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Animals Disease Models, Animal Endoplasmic Reticulum / metabolism Endosomes / physiology* Female HEK293 Cells HeLa Cells Humans Lipid Metabolism* Lipids Liposomes / metabolism Male Mice Mice, Inbred C57BL Mice, Inbred ICR Mice, Knockout Mitochondria Neurons / metabolism* Protein Domains Proteomics Recombinant Proteins Saccharomyces cerevisiae / metabolism Vesicular Transport Proteins / genetics Vesicular Transport Proteins / metabolism*
IF 12.121
DNA material pcDNA3.1_Lamp1_HA_GFP11 (RDB18655)