The Short Apical Membrane Half-life of Rescued ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Results from Accelerated Endocytosis of ΔF508-CFTR in Polarized Human Airway Epithelial Cells

Swiatecka‐Urban, Agnieszka; Brown, Andrea N.; Moreau‐Marquis, Sophie; Renuka, Janhavi; Coutermarsh, Bonita; Barnaby, Roxanna; Karlson, Katherine H.; Flotte, Terence R.; Fukuda, Mitsunori; Langford, George M.; Stanton, Bruce A.

doi:10.1074/jbc.m508944200

Cited by 170 publications

(204 citation statements)

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“…A detailed characterization of the mechanism for the decreased stability of F508del-CFTR confirmed an interaction between Rab11a and either wt-or F508del-CFTR in epithelial cells and reported that the siRNA knock-down of Rab11a decreases PM expression of CFTR. 17 Additionally, expression of DN Rab11a decreases PM expression of F508del-CFTR whereas overexpression of a constitutively active (CA) Rab11a variant increases these levels, consistent with the view that Rab11a facilitates the endocytic recycling of wt-CFTR and rescued F508del-CFTR in polarized human airway epithelial cells. 17 This process involves the motor protein Myosin Vb which is thought to be recruited to the recycling endosomes through interaction with the GTP-bound form of Rab11a.…”

Section: Regulation Of Cftr Membrane Trafficking By Rab Gtpasessupporting

confidence: 55%

“…17 Additionally, expression of DN Rab11a decreases PM expression of F508del-CFTR whereas overexpression of a constitutively active (CA) Rab11a variant increases these levels, consistent with the view that Rab11a facilitates the endocytic recycling of wt-CFTR and rescued F508del-CFTR in polarized human airway epithelial cells. 17 This process involves the motor protein Myosin Vb which is thought to be recruited to the recycling endosomes through interaction with the GTP-bound form of Rab11a. In fact, myosin Vb has been shown to facilitate CFTR recycling, but not endocytosis, in human airway cells.…”

Section: Regulation Of Cftr Membrane Trafficking By Rab Gtpasessupporting

confidence: 55%

“…Swiatecka-Urban and colleagues described a reduced apical membrane half-life for rescued F508del-CFTR when compared with wt-CFTR, 17 in what appeared to be an intrinsic problem of the mutant protein and not on the endocytosis machinery or on the possible upregulation of Rab5a (observed in other bronchial cell lines 18 ). A detailed characterization of the mechanism for the decreased stability of F508del-CFTR confirmed an interaction between Rab11a and either wt-or F508del-CFTR in epithelial cells and reported that the siRNA knock-down of Rab11a decreases PM expression of CFTR.…”

Section: Regulation Of Cftr Membrane Trafficking By Rab Gtpasesmentioning

confidence: 99%

“…The apparent Rab11 isoform-specificity, at least in the colon, in the regulation of CFTR and ENaC recycling 20,34 would support the targeting of Rab11a to decrease ENaC surface abundance while promoting the trafficking of rescued F508del via Rab11b-associated compartments. However, the role of Rab11a in regulating CFTR trafficking in the airways 17 would only advise for this isoform specific modulation in a tissue-specific manner. Furthermore, Rab11 is also known to play a crucial role in maintaining the proper distribution of the subapical Aquaporin 2 (AQP2) water channels and regulating the trafficking of AQP2.…”

Section: Rab Proteins As Putative Therapeutic Targetsmentioning

confidence: 99%

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Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

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The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis -the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF. Trafficking and Rab proteinsRegulation of ion and solute transport at the membrane of cells depends on the balance between the function of each channel or transporter and on the number of molecules present. 1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment. These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form. 2,3 The human subfamily contains more than 60 members that reversibly associate with different intracellular membranes, due to their post-translational modification with geranylgeranyl groups. 4 This association with membranes promotes interactions with other components of the trafficking machinery, such as coat components, motor proteins and SNAREs. 2 These characteristics make them relevant players in the control of membrane identity, in vesicle formation, motility and function, regulating the trafficking of many different classes of proteins, among which channels and transporters. 5

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Section: Regulation Of Cftr Membrane Trafficking By Rab Gtpasessupporting

confidence: 55%

Section: Regulation Of Cftr Membrane Trafficking By Rab Gtpasessupporting

confidence: 55%

Section: Regulation Of Cftr Membrane Trafficking By Rab Gtpasesmentioning

confidence: 99%

Section: Rab Proteins As Putative Therapeutic Targetsmentioning

confidence: 99%

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Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

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“…Ϫ cells stably transduced with WT CFTR (CFBE-WT) (25,26) were maintained in minimal essential medium supplemented with 10% fetal calf serum (HyClone), 50 units/ml penicillin, 50 g/ml streptomycin, 2 mM L-glutamine, and 0.5 g of puromycin and passaged every 3-4 days. CFBE-WT cells were transfected by electroporation; the contents of a nearly confluent 100-mm dish of CFBE-WT cells were used for each electroporation.…”

Section: Methodsmentioning

confidence: 99%

Cysteine String Protein Promotes Proteasomal Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Increasing Its Interaction with the C Terminus of Hsp70-interacting Protein and Promoting CFTR Ubiquitylation

Schmidt

Watts

Aridor

et al. 2009

Journal of Biological Chemistry

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Cysteine string protein (Csp) is a J-domain-containing protein whose overexpression blocks the exit of cystic fibrosis transmembrane conductance regulator (CFTR) from the endoplasmic reticulum (ER). Another method of blocking ER exit, the overexpression of Sar1-GTP, however, yielded twice as much immature CFTR compared with Csp overexpression. This finding suggested that Csp not only inhibits CFTR ER exit but also facilitates the degradation of immature CFTR. This was confirmed by treatment with a proteasome inhibitor, which returned the level of immature CFTR to that found in cells expressing Sar1-GTP only. CspH43Q, which does not interact with Hsc70/Hsp70 efficiently, did not promote CFTR degradation, suggesting that the pro-degradative effect of Csp requires Hsc70/Hsp70 binding/activation. In agreement with this, Csp overexpression increased the amount of Hsc70/Hsp70 co-immunoprecipitated with CFTR, whereas overexpression of CspH43Q did not. The Hsc70/Hsp70 binding partner C terminus of Hsp70-interacting protein (CHIP) can target CFTR for proteasome-mediated degradation. Csp overexpression also increased the amount of CHIP co-immunoprecipitated with CFTR. In addition, CHIP interacted directly with Csp, which was confirmed by in vitro binding experiments. Csp overexpression also increased CFTR ubiquitylation and reduced the half-life of immature CFTR. These findings indicate that Csp not only regulates the exit of CFTR from the ER, but that this action is accompanied by Hsc70/ Hsp70 and CHIP-mediated CFTR degradation.Cysteine string protein (Csp, DnaJC5) 2 is a member of the DnaJ/Hsp40 protein chaperone family (1, 2). Csp contains a short N-terminal sequence, followed by the J-domain, a linker region, and the central cysteine-rich region, which gives these proteins their name. The cysteine residues in this region are post-translationally modified by the palmitate groups that serve for the membrane attachment of Csp (3). This structure is followed by a C-terminal domain, which is the most variable region among the three Csp paralogs in the human genome.Csp was originally discovered as an abundant protein in presynaptic junctions of Drosophila neurons (4). Csps are expressed at high levels in neurons and in cell types involved in regulated exocytosis (5-7), where they have been shown to govern exocytic secretory functions. For example, depolarizationinduced synaptic vesicle exocytosis is impaired in neurons from Csp-deficient Drosophila (8), and Csp overexpression produced decreases in stimulated insulin release from ␤-cells and stimulated catecholamine release from chromaffin cells (9 -11). Deletion of the Csp gene proved to be lethal both in Drosophila and in mice causing a progressive, fatal sensorimotor disorder characterized by developing neurodegenerative changes (12, 13).As for other Hsp40 homologs, the J-domain is responsible for the ability of Csp to bind Hsc70/Hsp70 and stimulate its ATPase activity (14). Similar to other chaperone proteins, Csp can be found in many different protein complexes in the...

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Folding Biology of Cystic Fibrosis: A Consortium‐Based Approach to Disease

Balch¹,

Braakman²,

Brodsky³

et al. 2010

Protein Misfolding Diseases

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The Short Apical Membrane Half-life of Rescued ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Results from Accelerated Endocytosis of ΔF508-CFTR in Polarized Human Airway Epithelial Cells

Cited by 170 publications

References 103 publications

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Cysteine String Protein Promotes Proteasomal Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Increasing Its Interaction with the C Terminus of Hsp70-interacting Protein and Promoting CFTR Ubiquitylation

Folding Biology of Cystic Fibrosis: A Consortium‐Based Approach to Disease

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