CFTR-NHERF2-LPA₂ Complex in the Airway and Gut Epithelia.

Weiqiang Zhang,Anjaparavanda Naren,Yanhui Zhang,Zhihong Zhang

doi:10.3390/ijms18091896

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and cGMP-regulated chloride (Cl−) and bicarbonate (HCO3−) channel localized primarily at the apical plasma membrane of epithelial cells lining the airway, gut and exocrine glands, where it is responsible for transepithelial salt and water transport. Several human diseases are associated with altered CFTR channel function. Cystic fibrosis (CF) is caused by the absence or dysfunction of CFTR channel activity, resulting from mutations in the gene. Secretory diarrhea is caused by the hyperactivation of CFTR channel activity in the gastrointestinal tract. CFTR is a validated target for drug development to treat CF, and extensive research has been conducted to develop CFTR inhibitors for therapeutic interventions of secretory diarrhea. The intracellular processing, trafficking, apical membrane localization, and channel function of CFTR are regulated by dynamic protein–protein interactions in a complex network. In this paper, we review the current knowledge of a macromolecular complex of CFTR, Na+/H+ exchanger regulatory factor 2 (NHERF2), and lysophosphatidic acids (LPA) receptor 2 (LPA2) at the apical plasma membrane of airway and gut epithelial cells, and discuss its relevance in human physiology and diseases. We also explore the possibilities of targeting this complex to fine tune CFTR channel activity, with a hope to open up new avenues to develop novel therapies for CF and secretory diarrhea.

Highlights

Protein–protein interactions regulate virtually all cellular processes by promoting the proper cellular localization of regulatory partners and by facilitating the signaling through pathways to achieve exquisite spatiotemporal control
Based on the findings that (i) lysophosphatidic acids (LPA) levels are elevated in BAL fluid of subjects with Cystic fibrosis (CF) [36], (ii) CFTR-Na+/H+ exchanger regulatory factor 2 (NHERF2)-LPA2 complex at the apical plasma membrane of airway epithelial cells functionally couples LPA2-mediated signaling to CFTR channel function, and (iii) airway epithelial cells play a central role in regulating mucociliary clearance and modulating the innate and adaptive immune responses after infection [44], we explored the possibility of targeting CFTR-NHERF2-LPA2 complex to tackle two major pathologies associated with CF: loss or dysfunction of CFTR channel function, and excessive inflammation
CF and secretory diarrhea are two major human diseases associated with dysregulated CFTR channel activities

Summary

Introduction

Protein–protein interactions regulate virtually all cellular processes by promoting the proper cellular localization of regulatory partners and by facilitating the signaling through pathways to achieve exquisite spatiotemporal control. CFTR is a member of the ATP-binding cassette (ABC) transporter superfamily and consists of 1480 amino acids. CFTR is composed of two repeated motifs; each consisting of a six-helix membrane-spanning domain (MSD) and a cytosolic nucleotide binding domain (NBD). These two motifs are linked by a cytoplasmic regulatory (R) domain, which contains multiple consensus phosphorylation sites (Figure 1) [4,7,8]. CCFFTTRR iiss ccoommppoosseedd ooff ttwwoo mmeemmbbrraannee--ssppaannnniinngg ddoommaaiinnss ((MMSSDD11 aanndd MMSSDD22)),, ttwwoo nnuucclleeoottiiddee bbiinnddiinngg ddoommaaiinnss ((NNBBDD11 aanndd NNBBDD22)),, aanndd aa rreegguullaattoorryy ddoommaaiinn ((RR)). The R domain is a unique feature of CFTR within the ABC superfamily Both the amino and carboTxhyel tRerdmoimniaoinf CisFaTRunmiqeudeiafteeaittusrientoefraCcFtiToRnswwitihthinatwheidAeBvCarsieutpyeorffabminidlyi.ngBoptahrttnheersam[9i]n. IsnigtnhaislinargtitcoleC, wFTeRrecvhieawnntehlefcuunrcrteinotnk[n1o6w]. lIendgtheios faCrtFicTlRe,-NwHe EreRvFi2e-wLPtAhe ccuomrrepnletxkantotwheleadpgiecaolfpClaFsTmRa-NmHemERbrFa2n-LePoAf a2icrowmayplaenxdagt uthteepaipthicealliapllcaeslmlsaanmdemitsbrrealneevaonfcaeirinwhayumanadn gpuhtyseiopliothgeyliaanl dcedlilsseaasneds. iWtseraellseovaenxpcelorine thhuempoasnsipbihliytsieios,loagnyd panrodviddieseoausresp.eWrspeecatlisvoese,xopnlohroewthtoe ptaorsgseitbtihliitsiecso,manpdlepxrtoovfiidnee otuunrepCerFsTpReccthivaensn,eolnachtoivwityt,owtaitrhgeathtohpisectoomoppleenxutop fnienwe tauvneenCueFsTtRo cdheavnelnoepl ancotviveilttyh,ewraiptheuatihcsopfoertCoFoTpRe-nasusopcniaetwedadviesenauseess.to develop novel therapeutics for CFTR-associated diseases

Characterization of CFTR-NHERF2-LPA2 Complex

Disruption of NHERF2-LPA2 Interaction to Potentiate CFTR Channel Function

Findings

Conclusions