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Article ; Online: Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance.

Nguyen, Mai K L / Jose, Jaimy / Wahba, Mohamed / Bernaus-Esqué, Marc / Hoy, Andrew J / Enrich, Carlos / Rentero, Carles / Grewal, Thomas

International journal of molecular sciences

2022 Volume 23, Issue 13

Abstract: Cancer cells undergo drastic metabolic adaptions to cover increased bioenergetic needs, contributing to resistance to therapies. This includes a higher demand for cholesterol, which often coincides with elevated cholesterol uptake from low-density ... ...

Abstract	Cancer cells undergo drastic metabolic adaptions to cover increased bioenergetic needs, contributing to resistance to therapies. This includes a higher demand for cholesterol, which often coincides with elevated cholesterol uptake from low-density lipoproteins (LDL) and overexpression of the LDL receptor in many cancers. This implies the need for cancer cells to accommodate an increased delivery of LDL along the endocytic pathway to late endosomes/lysosomes (LE/Lys), providing a rapid and effective distribution of LDL-derived cholesterol from LE/Lys to other organelles for cholesterol to foster cancer growth and spread. LDL-cholesterol exported from LE/Lys is facilitated by Niemann-Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families. In addition, lysosomal membrane proteins, small Rab GTPases as well as scaffolding proteins, including annexin A6 (AnxA6), contribute to regulating cholesterol egress from LE/Lys. Here, we summarize current knowledge that links upregulated activity and expression of cholesterol transporters and related proteins in LE/Lys with cancer growth, progression and treatment outcomes. Several mechanisms on how cellular distribution of LDL-derived cholesterol from LE/Lys influences cancer cell behavior are reviewed, some of those providing opportunities for treatment strategies to reduce cancer progression and anticancer drug resistance.
MeSH term(s)	Antineoplastic Agents/analysis ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cholesterol/metabolism ; Cholesterol, LDL/metabolism ; Endosomes/metabolism ; Humans ; Lysosomes/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Niemann-Pick C1 Protein/metabolism ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Antineoplastic Agents ; Cholesterol, LDL ; Niemann-Pick C1 Protein ; Cholesterol (97C5T2UQ7J) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2022-06-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23137206
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Article ; Online: Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions.

Jose, Jaimy / Hoque, Monira / Engel, Johanna / Beevi, Syed S / Wahba, Mohamed / Georgieva, Mariya Ilieva / Murphy, Kendelle J / Hughes, William E / Cochran, Blake J / Lu, Albert / Tebar, Francesc / Hoy, Andrew J / Timpson, Paul / Rye, Kerry-Anne / Enrich, Carlos / Rentero, Carles / Grewal, Thomas

Scientific reports

2022 Volume 12, Issue 1, Page(s) 596

Abstract: Cholesterol is considered indispensable for cell motility, but how physiological cholesterol pools enable cells to move forward remains to be clarified. The majority of cells obtain cholesterol from the uptake of Low-Density lipoproteins (LDL) and here ... ...

Abstract	Cholesterol is considered indispensable for cell motility, but how physiological cholesterol pools enable cells to move forward remains to be clarified. The majority of cells obtain cholesterol from the uptake of Low-Density lipoproteins (LDL) and here we demonstrate that LDL stimulates A431 squamous epithelial carcinoma and Chinese hamster ovary (CHO) cell migration and invasion. LDL also potentiated epidermal growth factor (EGF) -stimulated A431 cell migration as well as A431 invasion in 3-dimensional environments, using organotypic assays. Blocking cholesterol export from late endosomes (LE), using Niemann Pick Type C1 (NPC1) mutant cells, pharmacological NPC1 inhibition or overexpression of the annexin A6 (AnxA6) scaffold protein, compromised LDL-inducible migration and invasion. Nevertheless, NPC1 mutant cells established focal adhesions (FA) that contain activated focal adhesion kinase (pY397FAK, pY861FAK), vinculin and paxillin. Compared to controls, NPC1 mutants display increased FA numbers throughout the cell body, but lack LDL-inducible FA formation at cell edges. Strikingly, AnxA6 depletion in NPC1 mutant cells, which restores late endosomal cholesterol export in these cells, increases their cell motility and association of the cholesterol biosensor D4H with active FAK at cell edges, indicating that AnxA6-regulated transport routes contribute to cholesterol delivery to FA structures, thereby improving NPC1 mutant cell migratory behaviour.
MeSH term(s)	Animals ; Annexin A6/metabolism ; CHO Cells ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Movement ; Cholesterol, LDL/metabolism ; Cricetulus ; Focal Adhesions/metabolism ; Humans ; Membrane Proteins/metabolism ; Niemann-Pick C1 Protein/metabolism ; rab7 GTP-Binding Proteins/metabolism
Chemical Substances	Annexin A6 ; Carrier Proteins ; Cholesterol, LDL ; Membrane Proteins ; Niemann-Pick C1 Protein ; STARD3 protein, human ; rab7 GTP-Binding Proteins
Language	English
Publishing date	2022-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-04584-y
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Article ; Online: Annexin A6 improves anti-migratory and anti-invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells.

Hoque, Monira / Elmaghrabi, Yasmin A / Köse, Meryem / Beevi, Syed S / Jose, Jaimy / Meneses-Salas, Elsa / Blanco-Muñoz, Patricia / Conway, James R W / Swarbrick, Alexander / Timpson, Paul / Tebar, Francesc / Enrich, Carlos / Rentero, Carles / Grewal, Thomas

The FEBS journal

2020 Volume 287, Issue 14, Page(s) 2961–2978

Abstract: Annexin A6 (AnxA6), a member of the calcium ( ... ...

Abstract	Annexin A6 (AnxA6), a member of the calcium (Ca
MeSH term(s)	Animals ; Annexin A6/genetics ; Annexin A6/metabolism ; Apoptosis ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Movement ; Cell Proliferation ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Neoplasm Invasiveness ; Neoplasms, Glandular and Epithelial/drug therapy ; Neoplasms, Glandular and Epithelial/metabolism ; Neoplasms, Glandular and Epithelial/pathology ; Phosphorylation ; Protein Kinase C-alpha/genetics ; Protein Kinase C-alpha/metabolism ; Protein Kinase Inhibitors/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Annexin A6 ; Protein Kinase Inhibitors ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Protein Kinase C-alpha (EC 2.7.11.13)
Language	English
Publishing date	2020-01-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15186
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Article ; Online: Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells.

Meneses-Salas, Elsa / García-Melero, Ana / Blanco-Muñoz, Patricia / Jose, Jaimy / Brenner, Marie-Sophie / Lu, Albert / Tebar, Francesc / Grewal, Thomas / Rentero, Carles / Enrich, Carlos

Cells

2020 Volume 9, Issue 5

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Annexin A6/metabolism ; CHO Cells ; Cholesterol/metabolism ; Cricetulus ; Endosomes/metabolism ; Endosomes/ultrastructure ; Feedback, Physiological ; Green Fluorescent Proteins/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Lysosomal-Associated Membrane Protein 2/metabolism ; Lysosomes/metabolism ; Lysosomes/ultrastructure ; Models, Biological ; Mutation/genetics ; Proteolysis
Chemical Substances	Annexin A6 ; Intracellular Signaling Peptides and Proteins ; Lysosomal-Associated Membrane Protein 2 ; NPC1 protein, human ; Green Fluorescent Proteins (147336-22-9) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2020-05-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9051152
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Article: Annexin A6 improves anti‐migratory and anti‐invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells

Hoque, Monira / Elmaghrabi, Yasmin A / Köse, Meryem / Beevi, Syed S / Jose, Jaimy / Meneses‐Salas, Elsa / Blanco‐Muñoz, Patricia / Conway, James R. W / Swarbrick, Alexander / Timpson, Paul / Tebar, Francesc / Enrich, Carlos / Rentero, Carles / Grewal, Thomas

FEBS journal. 2020 July, v. 287, no. 14

2020

Abstract: Annexin A6 (AnxA6), a member of the calcium (Ca²⁺) and membrane binding annexins, is known to stabilize and establish the formation of multifactorial signaling complexes. At the plasma membrane, AnxA6 is a scaffold for protein kinase Cα (PKCα) and GTPase‐ ...

Abstract	Annexin A6 (AnxA6), a member of the calcium (Ca²⁺) and membrane binding annexins, is known to stabilize and establish the formation of multifactorial signaling complexes. At the plasma membrane, AnxA6 is a scaffold for protein kinase Cα (PKCα) and GTPase‐activating protein p120GAP to promote downregulation of epidermal growth factor receptor (EGFR) and Ras/mitogen‐activated protein kinase (MAPK) signaling. In human squamous A431 epithelial carcinoma cells, which overexpress EGFR, but lack endogenous AnxA6, restoration of AnxA6 expression (A431‐A6) promotes PKCα‐mediated threonine 654 (T654)–EGFR phosphorylation, which inhibits EGFR tyrosine kinase activity. This is associated with reduced A431‐A6 cell growth, but also decreased migration and invasion in wound healing, matrigel, and organotypic matrices. Here, we show that A431‐A6 cells display reduced EGFR activity in vivo, with xenograft analysis identifying increased pT654‐EGFR levels, but reduced tyrosine EGFR phosphorylation compared to controls. In contrast, PKCα depletion in A431‐A6 tumors is associated with strongly reduced pT654 EGFR levels, yet increased EGFR tyrosine phosphorylation and MAPK activity. Moreover, tyrosine kinase inhibitors (TKIs; gefitinib, erlotinib) more effectively inhibit cell viability, clonogenic growth, and wound healing of A431‐A6 cells compared to controls. Likewise, the ability of AnxA6 to inhibit A431 motility and invasiveness strongly improves TKI efficacy in matrigel invasion assays. This correlates with a greatly reduced invasion of the surrounding matrix of TKI‐treated A431‐A6 when cultured in 3D spheroids. Altogether, these findings implicate that elevated AnxA6 scaffold levels contribute to improve TKI‐mediated inhibition of growth and migration, but also invasive properties in EGFR overexpressing human squamous epithelial carcinoma.
Keywords	GTPase-activating proteins ; calcium ; carcinoma ; cell growth ; cell viability ; epidermal growth factor receptors ; epithelium ; humans ; phosphorylation ; plasma membrane ; threonine ; tyrosine ; xenotransplantation
Language	English
Dates of publication	2020-07
Size	p. 2961-2978.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15186
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Article ; Online: Lack of Annexin A6 Exacerbates Liver Dysfunction and Reduces Lifespan of Niemann-Pick Type C Protein-Deficient Mice.

Meneses-Salas, Elsa / Garcia-Forn, Marta / Castany-Pladevall, Carla / Lu, Albert / Fajardo, Alba / Jose, Jaimy / Wahba, Mohamed / Bosch, Marta / Pol, Albert / Tebar, Francesc / Klein, Andrés D / Zanlungo, Silvana / Pérez-Navarro, Esther / Grewal, Thomas / Enrich, Carlos / Rentero, Carles

The American journal of pathology

2020 Volume 191, Issue 3, Page(s) 475–486

Abstract: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NPC disease primarily affects the brain, causing neuronal damage and affecting motor ... ...

Abstract	Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1 gene. NPC disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NPC disease is common. Recently, we found that the depletion of annexin A6 (ANXA6), which is most abundant in the liver and involved in cholesterol transport, ameliorated cholesterol accumulation in Npc1 mutant cells. To evaluate the potential contribution of ANXA6 in the progression of NPC disease, double-knockout mice (Npc1
MeSH term(s)	Animals ; Annexin A6/physiology ; Behavior, Animal ; Intracellular Signaling Peptides and Proteins/physiology ; Liver Diseases/etiology ; Liver Diseases/metabolism ; Liver Diseases/pathology ; Longevity ; Mice ; Mice, Knockout
Chemical Substances	Annexin A6 ; Anxa6 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Npc1 protein, mouse
Language	English
Publishing date	2020-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2020.12.009
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Article ; Online: Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice.

Alvarez-Guaita, Anna / Blanco-Muñoz, Patricia / Meneses-Salas, Elsa / Wahba, Mohamed / Pollock, Abigail H / Jose, Jaimy / Casado, Mercedes / Bosch, Marta / Artuch, Rafael / Gaus, Katharina / Lu, Albert / Pol, Albert / Tebar, Francesc / Moss, Stephen E / Grewal, Thomas / Enrich, Carlos / Rentero, Carles

Hepatology (Baltimore, Md.)

2020 Volume 72, Issue 6, Page(s) 2149–2164

Abstract: Background and aims: Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose ... ...

Abstract	Background and aims: Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate-limiting step in this pathway. Na Approach and results: Utilizing AnxA6 knockout mice (AnxA6 Conclusions: We conclude that the lack of AnxA6 compromises alanine-dependent GNG and liver regeneration in mice.
MeSH term(s)	Animals ; Annexin A6/genetics ; Annexin A6/metabolism ; Cell Membrane/metabolism ; Disease Models, Animal ; Gluconeogenesis/physiology ; Glucose/metabolism ; Glycolysis/physiology ; Hepatectomy ; Hepatocytes/metabolism ; Humans ; Liver/cytology ; Liver/metabolism ; Liver/surgery ; Liver Regeneration/physiology ; Male ; Mice ; Mice, Knockout
Chemical Substances	Annexin A6 ; Anxa6 protein, mouse ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.31232
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Article: Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

Cellular and molecular life sciences. 2020 July, v. 77, no. 14

2020

Abstract: 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 ... ...

Abstract	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 ; cholesterol acyltransferase ; electron microscopy ; endosomes ; exports ; mutants ; phenotype
Language	English
Dates of publication	2020-07
Size	p. 2839-2857.
Publishing place	Springer International Publishing
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-019-03330-y
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Article ; Online: Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells.

Cellular and molecular life sciences : CMLS

2019 Volume 77, Issue 14, Page(s) 2839–2857

Abstract	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.
MeSH term(s)	Animals ; Annexin A6/genetics ; CHO Cells ; Carrier Proteins/genetics ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Cholesterol/genetics ; Cholesterol/metabolism ; Cricetulus ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/metabolism ; Endosomes/genetics ; Endosomes/metabolism ; GTPase-Activating Proteins/genetics ; Humans ; Membrane Proteins/genetics ; Niemann-Pick Disease, Type C/genetics ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick Disease, Type C/pathology ; Protein Domains/genetics ; Protein Transport/genetics ; RNA, Small Interfering/genetics ; rab GTP-Binding Proteins/genetics
Chemical Substances	Annexin A6 ; Carrier Proteins ; GTPase-Activating Proteins ; Membrane Proteins ; RNA, Small Interfering ; STARD3 protein, human ; TBC1D15 protein, human ; rab7 protein (152989-05-4) ; Cholesterol (97C5T2UQ7J) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2019-10-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-019-03330-y
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