Genetic inactivation of ClC-5, a voltage-gated
chloride channel prominently expressed in the kidney, leads to
proteinuria because of defective apical endocytosis in proximal tubular cells. Because
thyroid hormone secretion depends on apical endocytosis of
thyroglobulin (Tg), we investigated whether ClC-5 is expressed in the thyroid and affects its function, using Clcn5-deficient knockout (KO) mice. We found that ClC-5 is highly expressed in wild-type mouse thyroid ( approximately 40% of
mRNA kidney level). The
protein was immunolocalized at the apical pole of thyrocytes. In
Percoll gradients, ClC-5 overlapped with plasma membrane and early endosome markers, but best codistributed with the late endosomal marker, Rab7. ClC-5 KO mice were euthyroid (normal T4 and TSH serum levels) but developed a
goiter with parallel
iodine and Tg accumulation (i.e. normal Tg iodination level). When comparing ClC-5 KO with wild-type mice, thyroid 125I uptake after 1 h was doubled, incorporation into Tg was decreased by approximately 2-fold, so that
trichloroacetic acid-soluble 125I increased approximately 4-fold. Enhanced 125I- efflux upon
perchlorate and presence of 125I-Tg as autoradiographic rings at follicle periphery demonstrated delayed
iodide organification. Endocytic trafficking of 125I-Tg toward lysosomes was not inhibited. Expression of pendrin, an I-/Cl- exchanger involved in apical
iodide efflux, was selectively decreased by 60% in KO mice at
mRNA and
protein levels. Thus, ClC-5 is well expressed in the thyroid but is not critical for apical endocytosis, contrary to the kidney. Instead, the
goiter associated with ClC-5 KO results from impaired rate of apical
iodide efflux by down-regulation of pendrin expression.