info:eu-repo/semantics/article
The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane
Fecha
2021-07Registro en:
Martín, Mariano; Salleron, Lisa; Peyret, Victoria; Geysels, Romina Celeste; Darrouzet, Elisabeth; et al.; The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane; Federation of American Societies for Experimental Biology; FASEB Journal; 35; 8; 7-2021; 1-13
0892-6638
1530-6860
CONICET Digital
CONICET
Autor
Martín, Mariano
Salleron, Lisa
Peyret, Victoria
Geysels, Romina Celeste
Darrouzet, Elisabeth
Lindenthal, Sabine
Bernal Barquero, Carlos Eduardo
Masini Repiso, Ana María
Pourcher, Thierry
Nicola, Juan Pablo
Resumen
The sodium/iodide symporter (NIS) expresses at the basolateral plasma membrane of the thyroid follicular cell and mediates iodide accumulation required for normal thyroid hormonogenesis. Loss-of-function NIS variants cause congenital hypothyroidism due to impaired iodide accumulation in thyroid follicular cells underscoring the significance of NIS for thyroid physiology. Here we report novel findings derived from the thorough characterization of the nonsense NIS mutant p.R636* NIS—leading to a truncated protein missing the last eight amino acids—identified in twins with congenital hypothyroidism. R636* NIS is severely mislocalized into intracellular vesicular compartments due to the lack of a conserved carboxy-terminal type 1 PDZ-binding motif. As a result, R636* NIS is barely targeted to the plasma membrane and therefore iodide transport is reduced. Deletion of the PDZ-binding motif causes NIS accumulation into late endosomes and lysosomes. Using PDZ domain arrays, we revealed that the PDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS by a PDZ-PDZ interaction. Furthermore, in CRISPR/Cas9-based SCRIB deficient cells, NIS expression at the basolateral plasma membrane is compromised, leading to NIS localization into intracellular vesicular compartments. We conclude that the PDZ-binding motif is a plasma membrane retention signal that participates in the polarized expression of NIS by selectively interacting with the PDZ-domain containing protein SCRIB, thus retaining the transporter at the basolateral plasma membrane. Our data provide insights into the molecular mechanisms that regulate NIS expression at the plasma membrane, a topic of great interest in the thyroid cancer field considering the relevance of NIS-mediated radioactive iodide therapy for differentiated thyroid carcinoma.