Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) disrupt epithelial secretion and cause cystic fibrosis (CF). Available CFTR modulators provide only modest clinical benefits, so alternative therapeutic targets are being explored. The anion-conducting transporter solute carrier family 26 member 9 (SLC26A9) is a promising candidate, but its functional expression is drastically reduced in cells that express the most common CF-associated CFTR variant, F508del-CFTR, through mechanisms that remain incompletely understood. Here, we examined the metabolic stability and location of SLC26A9 and its relationship to CFTR. Compared with SLC26A9 levels in BHK cells expressing SLC26A9 alone or with WT-CFTR, co-expression of SLC26A9 with F508del-CFTR reduced total and plasma membrane levels of SLC26A9. Proteasome inhibitors increased SLC26A9 immunofluorescence in primary human bronchial epithelial cells (pHBEs) homozygous for F508del-CFTR but not in non-CF pHBEs, suggesting that F508del-CFTR enhances proteasomal SLC26A9 degradation. Apical SLC26A9 expression increased when F508del-CFTR trafficking was partially corrected by low temperature or with the CFTR modulator VX-809. The immature glycoforms of SLC26A9 and CFTR co-immunoprecipitated, consistent with their interaction in the endoplasmic reticulum (ER). Transfection with increasing amounts of WT-CFTR cDNA progressively increased SLC26A9 levels in F508del-CFTR-expressing cells, suggesting that WT-CFTR competes with F508del-CFTR for SLC26A9 binding. Immunofluorescence staining of endogenous SLC26A9 and transfection of a 3HA-tagged construct into well-differentiated cells revealed that SLC26A9 is mostly present at tight junctions. We conclude that SLC26A9 interacts with CFTR in both the ER and Golgi and that its interaction with F508del-CFTR increases proteasomal SLC26A9 degradation.
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http://dx.doi.org/10.1074/jbc.RA119.010192 | DOI Listing |
J Biol Chem
December 2024
Physiology & Biomedical Engineering, Mayo Clinic College of Medicine & Science, Rochester, MN, 55906; Nephrology & Hypertension, Mayo Clinic College of Medicine & Science, Rochester, MN, 55906. Electronic address:
The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic STAS domain and the R domain of CFTR. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in non-mammals. Despite the numerous studies involving the STAS domains in SLC26 proteins, the role of the disordered loop region has not been identified.
View Article and Find Full Text PDFPeerJ
November 2024
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Background: Colorectal cancer is a common condition with an uncommon burden of disease, heterogeneity in manifestation, and no definitive treatment in the advanced stages. Renewed efforts to unravel the genetic drivers of colorectal cancer progression are paramount. Early-stage detection contributes to the success of cancer therapy and increases the likelihood of a favorable prognosis.
View Article and Find Full Text PDFAging (Albany NY)
June 2024
Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Mitophagy serves as a critical mechanism for tumor cell death, significantly impacting the progression of tumors and their treatment approaches. There are significant challenges in treating patients with head and neck squamous cell carcinoma, underscoring the importance of identifying new targets for therapy. The function of mitophagy in head and neck squamous carcinoma remains uncertain, thus investigating its impact on patient outcomes and immunotherapeutic responses is especially crucial.
View Article and Find Full Text PDFClin Chim Acta
July 2024
Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children's Hospital, Jackson Health System, Miami, FL 33136, USA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:
Background And Aims: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease can be quite variable suggesting modifier genes play an important role.
Materials And Methods: Exome sequencing was performed on six individuals carrying homozygous deltaF508 for CFTR genotype but present with rapidly progressing CF (RPCF).
Biophys J
June 2024
Graduate School of Information Sciences, Tohoku University, Sendai, Miyagi, Japan; Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan; Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Miyagi, Japan. Electronic address:
The anion exchanger solute carrier family 26 (SLC26)A9, consisting of the transmembrane (TM) domain and the cytoplasmic STAS domain, plays an essential role in regulating chloride transport across cell membranes. Recent studies have indicated that C-terminal helices block the entrance of the putative ion transport pathway. However, the precise functions of the STAS domain and C-terminal helix, as well as the underlying molecular mechanisms governing the transport process, remain poorly understood.
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