Annexins: Ca2+ Effectors Determining Membrane Trafficking in the Late Endocytic Compartment

Enrich, Carlos; Rentero, Carles; Meneses‐Salas, Elsa; Tebar, Francesc; Grewal, Thomas

doi:10.1007/978-3-319-55858-5_14

Cited by 21 publications

(17 citation statements)

References 233 publications

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“…Depletion of AnxA6 could stabilize StARD3/VAP-A and Rab7/protrudin/VAP-A complexes, ensuring re-establishment of MCS between the ER and late endosomes, and eventually the transfer of late endosome-cholesterol to the ER in cells with non-functional NPC1. Although several annexins contribute to endosomal membrane dynamics [62,96,97], only the AnxA1/S100A11 protein complex has yet been associated with MCS formation [90]. While AnxA2 and AnxA6 are also well known to bind S100 proteins, to our knowledge there is no data linking AnxA2 with MCS [90,98].…”

Section: Discussionmentioning

confidence: 92%

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: Discussionmentioning

confidence: 92%

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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“…As excess amounts of cellular unesterified (free) cholesterol are cytotoxic, cells have developed sophisticated circuits to regulate its intracellular sorting, trafficking ensure proper LE/Lys functioning and provide opportunity to control the intracellular movement of lipids, in particular, cholesterol, into and out of the LE/Lys compartment. Indeed, we and others demonstrated that AnxA1, A2, A6, and A8 contribute to cholesterol trafficking along endo-and exocytic pathways, suggesting that this subset of annexins, as well as other Ca 2+ -binding proteins, are good candidates for achieving regulatory tasks not only in regard to cellular cholesterol homeostasis, but also cholesterol-dependent activities in LE/Lys such as autophagy [23].…”

Section: Introductionmentioning

confidence: 79%

Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells

Meneses‐Salas

García-Melero

Blanco‐Muñoz

et al. 2020

Cells

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We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann–Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 inhibition, using U18666A, were not due to upregulated AnxA6 mRNA expression, but caused by defects in AnxA6 protein degradation. Two KFERQ-motifs are believed to target AnxA6 to lysosomes for chaperone-mediated autophagy (CMA), and we hypothesized that the cholesterol accumulation in endolysosomes (LE/Lys) triggered by the NPC1 inhibition could interfere with the CMA pathway. Therefore, AnxA6 protein amounts and cholesterol levels in the LE/Lys (LE-Chol) compartment were analyzed in NPC1 mutant cells ectopically expressing lysosome-associated membrane protein 2A (Lamp2A), which is well known to induce the CMA pathway. Strikingly, AnxA6 protein amounts were strongly decreased and coincided with significantly reduced LE-Chol levels in NPC1 mutant cells upon Lamp2A overexpression. Therefore, these findings suggest Lamp2A-mediated restoration of CMA in NPC1 mutant cells to lower LE-Chol levels with concomitant lysosomal AnxA6 degradation. Collectively, we propose CMA to permit a feedback loop between AnxA6 and cholesterol levels in LE/Lys, encompassing a novel mechanism for regulating cholesterol homeostasis in NPC1 disease.

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“…ANXA5 and ANXA6 mediate fusion of autophagosomes/LY and LE/LY, respectively [73]. Other Annexins have been implicated in vesicular membrane trafficking, highlighting them as potential candidates to bridge TPC function and associated SNARE complex activity [72][73][74]. ANKRD27, a regulator of SNARE-and Rab-dependent melanosome enzyme trafficking is also a TPC2 interaction candidate [67].…”

Section: Tpc2mentioning

confidence: 99%

The protein interaction networks of mucolipins and two-pore channels

Krogsaeter¹,

Biel

Wahl‐Schott

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Background:The endolysosomal, non-selective cation channels, two-pore channels (TPCs) and mucolipins (TRPMLs), regulate intracellular membrane dynamics and autophagy. While partially compensatory for each other, isoform-specific intracellular distribution, cell-type expression patterns, and regulatory mechanisms suggest different channel isoforms confer distinct properties to the cell. Scope of review: Briefly, established TPC/TRPML functions and interaction partners ('interactomes') are discussed. Novel TRPML3 interactors are shown, and a meta-analysis of experimentally obtained channel interactomes conducted. Accordingly, interactomes are compared and contrasted, and subsequently described in detail for TPC1, TPC2, TRPML1, and TRPML3. Major conclusions: TPC interactomes are well-defined, encompassing intracellular membrane organisation proteins. TRPML interactomes are varied, encompassing cardiac contractility-and chaperone-mediated autophagy proteins, alongside regulators of intercellular signalling. General significance: Comprising recently proposed targets to treat cancers, infections, metabolic disease and neurodegeneration, the advancement of TPC/TRPML understanding is of considerable importance. This review proposes novel directions elucidating TPC/TRPML relevance in health and disease.

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Annexins: Ca2+ Effectors Determining Membrane Trafficking in the Late Endocytic Compartment

Cited by 21 publications

References 233 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

Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells

The protein interaction networks of mucolipins and two-pore channels

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