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
|
Resource |
DNA material |
pcDNA3.1_Lamp1_HA_GFP11 (RDB18655) |