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.
Highlights
Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs)
Protrudin was shown to regulate endosome trafficking through interaction with the GTP-bound form of Rab[7], suggesting that it might control the direction of endosome sorting and endosome maturation by changing its partner Rab proteins in complex with GTP or GDP16,18,44
We have identified PDZD8 as a key binding partner of protrudin and shown that the protrudin-PDZD8 system promotes the formation of MCSs between the ER and LyLEs
Summary
Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs). 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. The identity of tethering factors at MCSs and the mechanisms by which these structures regulate cellular processes—such as lipid transfer, calcium ion homeostasis, and organelle dynamics—have remained largely unclear, [1,2,3,4,5,6]. Neurons with HSP-associated mutations of the genes for spastin or REEP1, both of which contain an HP domain, were recently shown to manifest grossly enlarged LyLEs and lysosomal dysfunction as a result of defects in ER-LyLE MCSs and impaired endosomal homeostasis[11,30]. We find that the protrudin-PDZD8 system is essential for the establishment of neuronal polarity and the maintenance of neuronal integrity
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