TAT1 (SLC26A8), molecular partner and activator of CFTR in the sperm, at the crossroad of human male infertility and cystic fibrosis – MUCOFERTIL

The Solute carrier 26 (SLC26) family members are membrane anion exchangers that transport monovalent and/or divalent anions, including sulfate (SO42-), chloride (Cl-), iodide (I-), bicarbonate (HCO3-) and oxalate (Ox2-) ions. Their activity is essential to various physiological functions and differentiation processes; hence, in human, four diseases have been associated to "loss of function" mutations in SLC26 genes (i.e. Pendred syndrome, deafness, diastrophic dysplasia, congenital chloride diarrhoea). We previously characterized the TAT1 (SLC26A8) protein specifically expressed in male germ cells and showed that in the mouse, deletion of Tat1 caused male sterility due to a lack of sperm motility, impaired capacitation and structural defects of the flagella. Interestingly we have found that in mature sperm, TAT1 primarily locates to the annulus, a ring-shaped structure located at the junction of the midpiece and the principal piece of the flagellum. Ca2+, Cl- and HCO3- influxes are known to trigger sperm capacitation events required for oocyte fertilization. In particular, these three ions are responsible for increasing the intracellular cAMP concentration and the subsequent activation of PKA and phosphorylation cascades essential for sperm capacitation. The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is expressed in mature sperm and has been shown to contribute to Cl- and HCO3- movements during capacitation. Interestingly, we recently found that, like several SLC26 transporters, TAT1 physically interacts with CFTR and strongly stimulates its activity. In support to a role of TAT1 in sperm capacitation, we have also shown that Tat1 inactivation in the mouse resulted in deregulation of the intracellular cAMP content and impairment of PKA-dependent downstream phosphorylation cascades. Altogether, these results suggest that TAT1 and CFTR may form a molecular complex involved in the regulation of Cl- and HCO3- fluxes during sperm capacitation. Therefore in humans, mutations in CFTR and/or TAT1 genes could be causes of asthenozoospermia and low fertilizing capacity of sperm. In line with these findings, the present program aims at i/ better defining the physiological function and regulation of TAT1 and CFTR in sperm, ii/ analyzing the sequence of TAT1, CFTR and other connected genes in a cohort of asthenozoospermic patients, and iii/ initiating structural and pharmacological studies in order to identify bioactive compounds targeting the TAT1 protein.