LDL Cholesterol Recycles to the Plasma Membrane via a Rab8a-Myosin5b-Actin-Dependent Membrane Transport Route

Kanerva, Kristiina; Uronen, Riikka-Liisa; Blom, Tomas; Li, Shiqian; Bittman, Robert; Lappalainen, Pekka; Peränen, Johan; Raposo, Graça; Ikonen, Elina

doi:10.1016/j.devcel.2013.09.016

Cited by 96 publications

(116 citation statements)

References 57 publications

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“…Although Arf6 and Rab8 have been shown to colocalize in tubular structures (Hattula et al, 2006), we did not observe colocalization of Rab8 and Tiam1 in tubules, but mainly at protrusion sites in the plasma membrane, suggesting that Rab8 acts downstream of Arf6 to promote Rac1 activation by mediating docking and fusion of Tiam1-carrying recycling endosomes. Interestingly, Rab8 promotes the delivery of cholesterol to the plasma membrane (Kanerva et al, 2013), which would provide cholesterol-rich membrane microdomains where Rac1 can activate its downstream effectors (Navarro-Lérida et al, 2012). In addition, Rab8 promotes Rac1-independent and RhoA-dependent disassembly of stress fibre.…”

Section: Discussionmentioning

confidence: 99%

A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP

Bravo‐Cordero

Cordani

Soriano

et al. 2016

Journal of Cell Science

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Rab8 is a small Ras-related GTPase that regulates polarized membrane transport to the plasma membrane. Here, we developed a high-content analysis (HCA) tool to dissect Rab8-mediated actin and focal adhesion reorganization that revealed that Rab8 activation significantly induced Rac1 and Tiam1 to mediate cortical actin polymerization and RhoA-dependent stress fibre disassembly. Rab8 activation increased Rac1 activity, whereas its depletion activated RhoA, which led to reorganization of the actin cytoskeleton. Rab8 was also associated with focal adhesions, promoting their disassembly in a microtubule-dependent manner. This Rab8 effect involved calpain, MT1-MMP (also known as MMP14) and Rho GTPases. Moreover, we demonstrate the role of Rab8 in the cell migration process. Indeed, Rab8 is required for EGF-induced cell polarization and chemotaxis, as well as for the directional persistency of intrinsic cell motility. These data reveal that Rab8 drives cell motility by mechanisms both dependent and independent of Rho GTPases, thereby regulating the establishment of cell polarity, turnover of focal adhesions and actin cytoskeleton rearrangements, thus determining the directionality of cell migration.

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Section: Discussionmentioning

confidence: 99%

A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP

Bravo‐Cordero

Cordani

Soriano

et al. 2016

Journal of Cell Science

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“…The majority of late-endosome-derived cholesterol is then delivered to the plasma membrane, while some of it is transported to the ER to enable feedback control or undergoes esterification for storage in lipid droplets in the form of cholesteryl esters. The routes and mechanisms by which late endosome-originating cholesterol reaches the plasma membrane are not clear, but as shown by our laboratory (Cubells et al, 2007;Reverter et al, 2014) and others (Kanerva et al, 2013;Urano et al, 2008), might involve transport through the ER, the transGolgi network (TGN) and recycling endosomes (Fig. 1A).…”

Section: Intracellular Trafficking Of Cholesterolmentioning

confidence: 99%

“…Niemann Pick C1 protein (NPC1) and Niemann Pick type C2 protein homolog (NPC2) bind to late-endosome-associated cholesterol and facilitate its export from late endosomes (Ikonen, 2006;Vance and Karten, 2014). Mutations in the genes encoding NPC1 or NPC2 inhibit the egress of cholesterol from late endosomes (Klein et al, 2006) and reduce its delivery to the Golgi, plasma membrane and recycling endosomes (Cubells et al, 2007;Kanerva et al, 2013;Reverter et al, 2014;Urano et al, 2008). Together, this triggers a dysfunction of membrane trafficking, which is associated with cardiovascular, neurological and lysosomal storage diseases (Cortes et al, 2013;De Matteis and Luini, 2011;Ikonen, 2006;Maxfield and Tabas, 2005).…”

Section: Intracellular Trafficking Of Cholesterolmentioning

confidence: 99%

“…Recently, Ikonen and co-workers identified the delivery of LDL-derived cholesterol from late endosomes to focal adhesions (Kanerva et al, 2013). As outlined above, cholesterol is essential for the functioning of SNAREs at the plasma membrane and one could envisage that the compromised motility and function of late endosome and lysosomes in lysosomal storage diseases such as The number of hydrophobic residues in the transmembrane domain according to: http://www.ch.embnet.org/software/TMPRED_form.html.…”

Section: Snare Proteins On Endomembranes Interact With Cholesterolmentioning

confidence: 99%

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Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

Enrich

Rentero

Hierro

et al. 2015

Journal of Cell Science

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The cell surface delivery of extracellular matrix (ECM) and integrins is fundamental for cell migration in wound healing and during cancer cell metastasis. This process is not only driven by several soluble NSF attachment protein (SNAP) receptor (SNARE) proteins, which are key players in vesicle transport at the cell surface and intracellular compartments, but is also tightly modulated by cholesterol. Cholesterol-sensitive SNAREs at the cell surface are relatively well characterized, but it is less well understood how altered cholesterol levels in intracellular compartments impact on SNARE localization and function. Recent insights from structural biology, protein chemistry and cell microscopy have suggested that a subset of the SNAREs engaged in exocytic and retrograde pathways dynamically 'sense' cholesterol levels in the Golgi and endosomal membranes. Hence, the transport routes that modulate cellular cholesterol distribution appear to trigger not only a change in the location and functioning of SNAREs at the cell surface but also in endomembranes. In this Commentary, we will discuss how disrupted cholesterol transport through the Golgi and endosomal compartments ultimately controls SNARE-mediated delivery of ECM and integrins to the cell surface and, consequently, cell migration.

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“…Recruitment of integrins to focal adhesions for cell migration requires cholesterol (18,19). Endocytosed LDL cholesterol from LEs controls the formation of focal adhesions at the leading edge of cells (20). Overall, dietary, genetic, and pathological changes in cholesterol metabolism seem to affect the migratory behavior of cancer cells (21)(22)(23).…”

mentioning

confidence: 99%

Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration

García-Melero

Reverter

Hoque

et al. 2016

Journal of Biological Chemistry

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Annexins are a family of proteins that bind to phospholipids in a calcium-dependent manner. Earlier studies implicated annexin A6 (AnxA6) to inhibit secretion and participate in the organization of the extracellular matrix. We recently showed that elevated AnxA6 levels significantly reduced secretion of the extracellular matrix protein fibronectin (FN). Because FN is directly linked to the ability of cells to migrate, this prompted us to investigate the role of AnxA6 in cell migration. Up-regulation of AnxA6 in several cell models was associated with reduced cell migration in wound healing, individual cell tracking and threedimensional migration/invasion assays. The reduced ability of AnxA6-expressing cells to migrate was associated with decreased cell surface expression of ␣V␤3 and ␣5␤1 integrins, both FN receptors. Mechanistically, we found that elevated AnxA6 levels interfered with syntaxin-6 (Stx6)-dependent recycling of integrins to the cell surface. AnxA6 overexpression caused mislocalization and accumulation of Stx6 and integrins in recycling endosomes, whereas siRNA-mediated AnxA6 knockdown did not modify the trafficking of integrins. Given our recent findings that inhibition of cholesterol export from late endosomes (LEs) inhibits Stx6-dependent integrin recycling and that elevated AnxA6 levels cause LE cholesterol accumulation, we propose that AnxA6 and blockage of LE cholesterol transport are critical for endosomal function required for Stx6-mediated recycling of integrins in cell migration.

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LDL Cholesterol Recycles to the Plasma Membrane via a Rab8a-Myosin5b-Actin-Dependent Membrane Transport Route

Cited by 96 publications

References 57 publications

A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP

A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration

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