PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria

Abstract

Endosomes are compositionally dynamic organelles that regulate signaling, nutrient status and organelle quality by specifying whether material entering the cells will be shuttled back to the cell surface or degraded by the lysosome. Recently, membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endosomes have emerged as important players in endosomal protein sorting, dynamics and motility. Here, we show that PDZD8, a Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domain-containing ER transmembrane protein, utilizes distinct domains to interact with Rab7-GTP and the ER transmembrane protein Protrudin and together these components localize to an ER-late endosome MCS. At these ER-late endosome MCSs, mitochondria are also recruited to form a three-way contact. Thus, our data indicate that PDZD8 is a shared component of two distinct MCSs and suggest a role for SMP-mediated lipid transport in the regulation of endosome function.

Relevance of Membrane Contact Sites in Cancer Progression

“…MAMs convey calcium signaling between the IP 3 R and the mitochondrial calcium uniporter (MCU), the channel responsible for Ca 2+ uptake into the mitochondrial matrix. Other recently described proteins that maintain MAM integrity are DJ-1 (oncoprotein encoded in PARK7 gene) ( Xu et al, 2018 ; Liu Y. et al, 2019 ; Basso et al, 2020 ) and PDZ domain-containing protein 8 (a synaptotagmin-like mitochondrial lipid-binding protein domain-containing ER transmembrane protein) that has been implicated in ER-dependent mitochondrial calcium homeostasis ( Hirabayashi et al, 2017 ; Elbaz-Alon et al, 2020 ), while pannexin 2 has been reported to sensitize cancer cells to apoptotic stimuli ( Le Vasseur et al, 2019 ). In triple-negative breast cancer (TNBC), MCU silencing disturbs calcium uptake, enhancing alternative pathways such as SOCE, whereas the reduction of mitochondrial calcium levels inhibits cell migration in cancer cell lines.…”

Lipid Transfer–Dependent Endosome Maturation Mediated by Protrudin and PDZD8 in Neurons

“…This analysis uncovered PDZD8, in addition to VAP-A and VAP-B, as a key binding partner of protrudin ( Elbaz-Alon et al, 2020 ; Shirane et al, 2020b ). An independent study also identified protrudin as a binding partner of PDZD8 ( Elbaz-Alon et al, 2020 ). PDZD8 is a mammalian paralog of yeast Mmm1, a subunit of the ER-mitochondrial encounter structure (ERMES) complex.…”

“…A differential proteomics analysis of brain extracts from wildtype and protrudin-deficient mice was performed to identify proteins that might function cooperatively with protrudin at ER-endosome MCSs. This analysis uncovered PDZD8, in addition to VAP-A and VAP-B, as a key binding partner of protrudin (Elbaz-Alon et al, 2020;Shirane et al, 2020b). An independent study also identified protrudin as a binding partner of PDZD8 (Elbaz-Alon et al, 2020).…”

“…PDZD8 also contains a CC domain that interacts with the GTP-bound form of Rab7, which localizes to LEs ( Chavrier et al, 1990 ; Raiborg et al, 2015 ; Guillen-Samander et al, 2019 ). In addition, a recent study suggested that the protrudin-PDZD8 complex resides at a microdomain at which three organelles—the ER, endosomes, and mitochondria—come into contact with each other ( Elbaz-Alon et al, 2020 ). However, further studies are needed to reveal the physiological function of such ER-endosome-mitochondrion contacts mediated by the protrudin-PDZD8 complex.…”

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

“…Recent studies implicated PDZD8, an ER-associated protein, and Protrudin together with the late endosomal protein Rab7 as main components of ER-endosome contact sites [292]. PDZD8 is also a component of the ER-mitochondria MCSs [293] and enables the recruitment of mitochondria to ER-endosomal MCS in order to regulate lipid transport and endosomal function [292]. Studying the significance of such complex inter-organellar interactions facilitated by multiple proteins in the context of axon growth and regeneration will be an interesting future area of research.…”