wtCFTR and deltaF508 traffic / Membrane expression (norm and CF)

wtCFTR and deltaF508 traffic/ Membrane expression (norm and CF)

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette transporter superfamily. It acts in apical part of the epithelial cells as a plasma-membrane cyclic AMP-activated chloride anion, bicarbonate anion and glutathione channel [1], [2], [3]. Cell surface expression of the CFTR is a highly regulated intracellular process [4], [5].

CFTR may be delivered to the cell surface from Golgi or via shot pathway from endosomes via different recycling endosomes [5], [6]. It is realized mainly via Rab-4 and/or Rab-11A-dependent mechanisms [7].

Endogenous Rab-11A, a member RAS oncogene family, in a complex with Myosin Vb and EH-domain containing 1 (EHD1) facilitates recycling of CFTR from recycling endosomes to the apical plasma membrane in polarized epithelial cells [8], [9], [10]. Rab-4 group of proteins belongs to RAS oncogene family which controls recycling events from endosome to the plasma membrane, fusion, and degradation inhibits CFTR chloride channel activity by diminishing its cell surface expression [11].

CFTR stabilization in plasma membrane depends on several proteins. Cyclic adenosine monophosphate cAMP-dependent protein kinase A (PKA) affects CFTR channel including stabilization in plasma membrane [12]. The anchoring protein Villin 2 (VIL2 (ezrin)) promotes PKA-to-CFTR interaction [13]. Moreover VIL2 (ezrin) itself exists in a complex with CFTR. This interaction is mediated by the Solute carrier family 9 member 3 regulator 2 (E3KARP (NHERF2)) - a PDZ-containing binding partner of CFTR [14]. Formation of a VIL2 (ezrin)/ E3KARP (NHERF2)/ CFTR complex enhances the efficacy of cAMP-mediated CFTR activation [14].

Beta-2 adrenergic receptor participates in CFTR stabilization as well. Stimulation of Beta-2 adrenergic receptor increases CFTR expression on apical membrane of epithelial cells as well as its association with Solute carrier family 9 member 3 regulator 1 (EBP50). Importantly this process is independent of the agonist-mediated PKA pathway [15], [16]. On the other hand, PKA-cat-mediated phosphorylation of CFTR strongly inhibits formation of the macromolecular complex consisting of Beta-2 adrenergic receptor/ EBP50/ CFTR [15]. The functional consequences of this disruption of this complex are elusive.

CFTR membrane expression is also regulated by the Tubulin/ EBP50/ Guanine nucleotide binding protein beta polypeptide 2-like 1 (RACK1)/ Protein kinase C epsilon (PKC-epsilon) pathway. PKC-epsilon phosphorylates CFTR and, thus, stabilize expression of CFTR in the apical plasma membrane of epithelial cells. [17], [18].

Moreover, Copper metabolism domain containing 1 (COMMD1) (Drevillion, L et al., The 21st annual north American cystic fibrosis conference, California, 2007), Filamin A and Filamin B [19] stabilize CFTR.

Syntaxin 1A/ Synaptosomal-associated protein 23kDa (SNAP-23) have negative influence on CFTR membrane expression [12], [20].

The most common CFTR mutation is the loss of a Phe residue at position 508 (deltaF508-CFTR). deltaF508-CFTR membrane expression is reduced compare with wtCFTR, but stabilization in plasma membrane deltaF508-CFTR and wtCFTR is regulated in a similar manner.

References:

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