Abstract
SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF. In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment.
Highlights
Academic Editor: SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins related to the phylogenetically older SLC26-SulP gene family
cystic fibrosis (CF) is a multi-organ disease, the most severe manifestations are observed in the lung, where the loss of the chloride and bicarbonate secretion mediated by CFTR dehydrates and acidifies the thin layer of fluid covering the airways and impairs the mucociliary clearance and the innate immunity, resulting in chronic infection, inflammation, and progressive structural and functional lung damage [9,10,11,12,13,14,15]
The correction of CF abnormalities can be achieved by restoring the function of CFTR with mutation-specific pharmacological treatments [16,17]
Summary
Academic Editor: SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins related to the phylogenetically older SLC26-SulP gene family. Three members of the family have been identified as disease-causing genes in different human genetic disorders: SLC26A2 in chondrodysplasias [3], SLC26A3 in chloride-losing diarrhea [4], and SLC26A4 in Pendred syndrome and hereditary deafness (DFNB4) [5,6,7] Based on their possible roles in anion transport, some members of the family, including SLC26A4 and SLC26A9, have been linked to cystic fibrosis (CF) as disease modifiers or potential therapeutic targets. Biomolecules 2022, 12, 202 potential alternative or synergic approach is to modulate the activity of other channels and transporters in order to stimulate CFTR-independent anion secretion In this context, SLC26A9 is under investigation as one of the most interesting targets. We summarized the various results dealing with SLC26A9 expression at the tissue, cellular, and subcellular levels; its structure and function as anion channel or transporter; its interaction and functional relationships with CFTR; and its role as gene modifier, and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment
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