title: The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation.
abstract: The Slc26 gene family encodes several conserved anion transporters implicated in human genetic disorders, including Pendred syndrome, diastrophic dysplasia and congenital chloride diarrhea. We previously characterized the TAT1 (testis anion transporter 1; SLC26A8) protein specifically expressed in male germ cells and mature sperm and showed that in the mouse, deletion of Tat1 caused male sterility due to a lack of sperm motility, impaired sperm capacitation and structural defects of the flagella. Ca(2+), Cl(-) and HCO(3)(-) influxes trigger sperm capacitation events required for oocyte fertilization; these events include the intracellular rise of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA)-dependent protein phosphorylation. The cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in mature sperm and has been shown to contribute to Cl(-) and HCO(3)(-) movements during capacitation. Furthermore, several members of the SLC26 family have been described to form complexes with CFTR, resulting in the reciprocal regulation of their activities. We show here that TAT1 and CFTR physically interact and that in Xenopus laevis oocytes and in CHO-K1 cells, TAT1 expression strongly stimulates CFTR activity. Consistent with this, we show that Tat1 inactivation in mouse sperm results in deregulation of the intracellular cAMP content, preventing the activation of PKA-dependent downstream phosphorylation cascades essential for sperm activation. These various results suggest that TAT1 and CFTR may form a molecular complex involved in the regulation of Cl(-) and HCO(3)(-) fluxes during sperm capacitation. In humans, mutations in CFTR and/or TAT1 may therefore be causes of asthenozoospermia and low fertilizing capacity of sperm.
authors: INSERM, U1016, Institut Cochin, Paris, France.
authors: Baptiste
authors: B
authors: Rode
authors: Thassadite
authors: T
authors: Dirami
authors: Naziha
authors: N
authors: Bakouh
authors: Marthe
authors: M
authors: Rizk-Rabin
authors: Caroline
authors: C
authors: Norez
authors: Pierre
authors: P
authors: Lhuillier
authors: Patrick
authors: P
authors: Lorès
authors: Mathilde
authors: M
authors: Jollivet
authors: Patricia
authors: P
authors: Melin
authors: Ilona
authors: I
authors: Zvetkova
authors: Thierry
authors: T
authors: Bienvenu
authors: Frédéric
authors: F
authors: Becq
authors: Gabrielle
authors: G
authors: Planelles
authors: Aleksander
authors: A
authors: Edelman
authors: Gérard
authors: G
authors: Gacon
authors: Aminata
authors: A
authors: Touré
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000502:physiology*; D017920:Antiporters / Q000502:physiology*; D001639:Bicarbonates / Q000378:metabolism; D019556:COS Cells; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D013075:Sperm Capacitation / Q000502:physiology*; D013081:Sperm Motility; D000076988:Sulfate Transporters; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D027321:Anion Transport Proteins; D017920:Antiporters; D001639:Bicarbonates; D002712:Chlorides; C524997:Slc26a8 protein, mouse; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases