Identification of MOSPD2, a novel scaffold for endoplasmic reticulum membrane contact sites

Mattia, Thomas Di; Wilhelm, Léa P; Ikhlef, Souade; Wendling, Corinne; Spehner, Danièle; Nominé, Yves; Giordano, Francesca; Mathelin, Carole; Drin, Guillaume; Tomasetto, Catherine; Alpy, Fabien

doi:10.15252/embr.201745453

Cited by 92 publications

(137 citation statements)

References 73 publications

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“…It was previously reported that enlarged and cholesterolladen late endosomes have impaired vesicular trafficking [35]. In addition, active Rab7 is required to promote MCS formation between late endosomes and lysosomes and the ER [12], providing protein-protein interactions within MCS for the bidirectional transfer of cholesterol and other lipids between late endosomes and ER [75,76]. Given elevated Rab7-GTP levels and increased late endosome motility in AnxA6-depleted NPC1 mutant cells (Fig.…”

Section: Stard3 Is Required To Rescue Late Endosome-cholesterol Expormentioning

confidence: 70%

“…Finally, we investigated whether the StARD3/VAP-A protein complex that can facilitate cholesterol transfer between late endosomes and the ER [75,76] could contribute to the rescue of late endosome-cholesterol export in CHO M12-A6ko cells. The ability of AnxA6 depletion to reduce late endosome-cholesterol accumulation in CHO M12 cells was lost upon StARD3 depletion and concomitantly, strongly interfered with neutral lipid accumulation in lipid droplets of CHO M12-A6ko cells (Fig.…”

Section: Stard3 Is Required To Rescue Late Endosome-cholesterol Expormentioning

confidence: 99%

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Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

Meneses‐Salas

García-Melero

Kanerva

et al. 2019

Cell. Mol. Life Sci.

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Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation. Keywords Cholesterol • Late endosomes • Rab7 • NPC1 • Annexin A6 • Membrane contact sites Abbreviations A431 Human epidermoid carcinoma cells ACAT Acyl-CoA:cholesterol acyltransferase AnxA6 Annexin A6 CHO Chinese hamster ovary CHO M12 NPC1 mutant CHO cell line CMA Chaperone-mediated autophagy ER Endoplasmic reticulum FYCO1 FYVE and coiled-coil domain containing 1 GST Glutathione S-transferase LE/Lys Late endosome/lysosome (endolysosomes) LPDS Lipoprotein-deficient serum MCS Membrane contact sites MEF Mouse embryonic fibroblasts MOSPD2 Motile sperm domain containing 2 NPC1 Niemann-Pick type C1 ORP1L Oxysterol-related protein 1L OSBP Oxysterol-binding protein PFO Perfringolysin O RILP Rab interacting lysosomal protein SREBP Sterol regulatory element binding protein StARD3 StAR-related lipid transfer domain-3 TBC1D15 TBC1 domain family member 15 WT Wild type VAP-A Vesicle-associated membrane protein-associated protein A Vps13 Vacuolar protein sorting-associated protein 13 Cellular and Molecular Life Sciences Elsa Meneses-Salas and Ana García-Melero contributed equally to this work.

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Section: Stard3 Is Required To Rescue Late Endosome-cholesterol Expormentioning

confidence: 70%

Section: Stard3 Is Required To Rescue Late Endosome-cholesterol Expormentioning

confidence: 99%

Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

Meneses‐Salas

García-Melero

Kanerva

et al. 2019

Cell. Mol. Life Sci.

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“…Much like cyclodextrin [35], thioperamide was able to partially correct the defect in the transcriptional regulation of two canonical cholesteroldependent genes, the LDL receptor and HMG CoA reductase in these NPC1 and NPC2 KO cells ( Fig 6A). By contrast, thioperamide treatment did not affect the expression levels of proteins involved in the transfer of cholesterol from endosome to the ER or in endosome-ER membrane contact sites ( Fig EV4), including FYCO1 [36], ANXA1 [37], STARD3/MLN64 [38], ORP1l, VAPA and VAPB [39,40].…”

Section: Thioperamide Reduces Cholesterol Overload In Npc Cellsmentioning

confidence: 90%

Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice

et al. 2019

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Most cells acquire cholesterol by endocytosis of circulating low‐density lipoproteins (LDLs). After cholesteryl ester de‐esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA‐approved compounds in a high‐content, image‐based screen of the endosomal lipids, lysobisphosphatidic acid and LDL‐derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann–Pick type C (NPC), as well as in liver of Npc1−/− mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.

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“…While the molecular details of this phenomenon await characterization, it is noteworthy that one of the most abundant proteins specifically enriched with NSP4 over the other viral proteins is MOSPD2 ( Fig. 3c), recently identified as a scaffolding protein for ER membrane contact sites 31 . Whether overexpression of NSP4 (or viral infection) disrupts ER integrity through MOSPD2 remains to be determined.…”

Section: Nsp7 and Nsp8mentioning

confidence: 98%

A SARS-CoV-2 – host proximity interactome

Samavarchi-Tehrani

Abdouni

Knight

et al. 2020

Preprint

118

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Viral replication is dependent on interactions between viral polypeptides and host proteins. Identifying virus-host protein interactions can thus uncover unique opportunities for interfering with the virus life cycle via novel drug compounds or drug repurposing. Importantly, many viral-host protein interactions take place at intracellular membranes and poorly soluble organelles, which are difficult to profile using classical biochemical purification approaches. Applying proximity-dependent biotinylation (BioID) with the fast-acting miniTurbo enzyme to 27 SARS-CoV-2 proteins in a lung adenocarcinoma cell line (A549), we detected 7810 proximity interactions (7382 of which are new for SARS-CoV-2) with 2242 host proteins (results available at covid19interactome.org). These results complement and dramatically expand upon recent affinity purification-based studies identifying stable host-virus protein complexes, and offer an unparalleled view of membrane-associated processes critical for viral production. Host cell organellar markers were also subjected to BioID in parallel, allowing us to propose modes of action for several viral proteins in the context of host proteome remodelling. In summary, our dataset identifies numerous high confidence proximity partners for SARS-CoV-2 viral proteins, and describes potential mechanisms for their effects on specific host cell functions.

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Identification of MOSPD2, a novel scaffold for endoplasmic reticulum membrane contact sites

Cited by 92 publications

References 73 publications

Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice

A SARS-CoV-2 – host proximity interactome

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