PDZD8 mediates a Rab7-dependent interaction of the ER with late endosomes and lysosomes

Abstract

Contacts between the endoplasmic reticulum (ER) and other membranes are hot spots for protein-mediated lipid transport between the 2 adjacent bilayers. Compiling a molecular inventory of lipid transport proteins present at these sites is a premise to the elucidation of their function. Here we show that PDZD8, an intrinsic membrane protein of the ER with a lipid transport module of the SMP domain family, concentrates at contacts between the ER and late endosomes/lysosomes, where it interacts with GTP-Rab7. These findings suggest that PDZD8 may cooperate with other proteins that function at the ER–endo/lysosome interface in coordinating endocytic flow with lipid transport between endocytic membranes and the ER.

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

“…Together these data indicate that ER-localized PDZD8 is recruited to late endosomes in a manner dependent on GTP-activated Rab7. These observations are consistent with a recent study published while this work was in review reporting that PDZD8 and Rab7-GTP are enriched at ER-late endosome contact sites 30 .…”

A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export

“…10b). At least three Rab7 effectors -ORP1L, Protrudin (ZFYVE27) and PDZD8have been involved in ERto-LE MCS formation 19,20,58,59 and Rab7 itself has been implicated in ER-to-mitochondria MCS formation 60 . MCS are of key importance for rapid inter-organelle lipid exchange, yet whether Rab7-mediated MCS are involved in cholesterol transfer remains controversial.…”

Maintaining social contacts: The physiological relevance of organelle interactions

“…In mammalian neurons, PDZD8 has been proposed as an alternative ER-mitochondria tether that is required for the mitochondrial uptake of Ca 2+ following its stimulated release from the ER in response to synaptic activation, to regulate cytosolic Ca 2+ dynamics [ 60 ] ( Table 1 ). However, despite initially being characterised as a functional orthologue of the yeast ERMES component Mmm1, there is increasing evidence that PDZD8 may be only distantly related to Mmm1 [ 61 ], and may in fact predominantly localize to ER-late endosome/lysosome contacts [ 62 ].…”

“…– Unknown protein (ER) tether Dendritic Ca 2+ homeostasis in mammalian neurons? [ 60 , 62 ] Mmm1, Mdm12 and Mdm34 (ERMES, MITO), VPS13 (yeast) Lipid transfer; phospholipid synthesis [ 33 , 70 , 71 ] VPS13A (MITO) – VAP (ER) Lipid transfer [ 73 , 127 ] PTPIP51 (MITO) – ORP5/8 (ER) Transport of phosphatidylserine from the ER to MITO [ 78 , 79 ] NLRP3 (ER) – MAVS (MITO) Immune signalling and inflammation [ [82] , [83] , [84] , [85] ] PTPIP51 (MITO) – VAPB (ER) tether Autophagosome formation/autophagy [ [87] , [88] , [89] ] Mitochondria – lysosome Tethers unknown Regulation of mitochondrial dynamics/fission [ 41 ] STARD3 (LYS) – tether? Cholesterol transport to MITO (compensatory mechanism for impaired LYS-ER cholesterol transport) [ 109 ] Regulated by RAB7, TBC1D15 (binds FIS1 at MITO) [ 103 , 105 , 106 ] DMT1 (ENDO/LYS, MITO) Iron transport from ENDO/LYS to MITO [ [119] , [120] , [121] , [122] ] Mitochondria – lipid droplets SNAP23, Unknown tether Lipid transfer between LD and MITO for mitochondrial β-oxidation; energy metabolism [ 124 , ...…”