The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane

MARTIN, M; SALLERON, L; PEYRET, V; GEYSELS, RC; DARROUZET, E; LINDENTHAL, S; BERNAL BARQUERO, CE; MASINI-REPISO, AM; POURCHER, T; NICOLA, JP

FASEB JOURNAL

FEDERATION AMER SOC EXP BIOL

Lugar: Bethesda; Año: 2021

0892-6638

The sodium/iodide symporter(NIS) expresses at the basolateral plasma membrane of the thyroid follicularcell and mediates iodide accumulation required for normal thyroidhormonogenesis. Loss-of-function NIS variants cause congenital hypothyroidismdue to impaired iodide accumulation in thyroid follicular cells underscoringthe significance of NIS for thyroid physiology. Here we report novel findingsderived from the thorough characterization of the nonsense NIS mutant p.R636*NIS?leading to a truncated protein missing the last eight aminoacids?identified in twins with congenital hypothyroidism. R636* NIS is severelymislocalized into intracellular vesicular compartments due to the lack of aconserved carboxy-terminal type 1 PDZ-binding motif. As a result, R636* NIS isbarely targeted to the plasma membrane and therefore iodide transport isreduced. Deletion of the PDZ-binding motif causes NIS accumulation into lateendosomes and lysosomes. Using PDZ domain arrays, we revealed that thePDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS by aPDZ-PDZ interaction. Furthermore, in CRISPR/Cas9-based SCRIB deficient cells, NISexpression at the basolateral plasma membrane is compromised, leading to NISlocalization into intracellular vesicular compartments. We conclude that thePDZ-binding motif is a plasma membrane retention signal that participates inthe polarized expression of NIS by selectively interacting with the PDZ-domaincontaining protein SCRIB, thus retaining the transporter at the basolateralplasma membrane. Our data provide insights into the molecularmechanisms that regulate NIS expression at the plasma membrane, a topic of great interest in the thyroid cancer fieldconsidering the relevance of NIS-mediated radioactive iodidetherapy for differentiated thyroid carcinoma.Keywords: Dyshormonogenic congenitalhypothyroidism, Iodide transport defect, Sodium/iodide symporter (NIS),PDZ-binding motif, PDZ domain-containing protein SCRIB.