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

Abstract

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/Cas9based 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 2 of 13 | MARTÍN eT Al.

HIF‐1α regulates the cell viability in radioiodine‐resistant papillary thyroid carcinoma cells induced by hypoxia through PKM2/NF‐κB signaling pathway

“…44 NIS was expressed at the plasma membrane of thyroid cells and mediated the cell sensitiveness and accumulation of 131 I. 45 In refractory-TC, NIS expression is defective, resulting in impaired group. Meanwhile, the levels of cell proliferation indicators (Ki67 and MMP-9) were significantly decreased and NIS expression was significantly increased both in vitro and in vivo, which is accordance with the previous studies.…”

Targeting GLI1 Transcription Factor for Restoring Iodine Avidity with Redifferentiation in Radioactive-Iodine Refractory Thyroid Cancers

“…On the other hand, recognition of ADP-ribosylation factor 4 (ARF4) by VAPK motif in the NIS C-terminus, regulation of SRC/RAC1/PAK1/PIP5K/EZRIN pathway, activation of RAC1 via MAPK inhibition, application of transient receptor potential vanilloid type 1 (TRPV1) agonist and others were shown to promote NIS functionality and trafficking towards the cell membrane [ 41 , 42 , 43 , 44 , 45 ]. Recently, an article suggested the role of protospacer adjacent motif (PDZ)—PDZ interaction which means PDZ-domain containing protein SCRIB binds to the carboxy-terminus of NIS to localize at proper basolateral plasma membrane [ 46 ]. These findings indicate that membrane targeting of NIS is also important, as much as an increase in NIS expression to revert RAI-refractory thyroid cancer into RAI-sensitive thyroid cancer.…”

The Molecular Basis for Radioiodine Therapy

“…The sodium/iodide symporter (NIS) is the key plasma membrane glycoprotein, which is located at the basolateral surface of the thyroid follicular cell that mediates active iodide transport from the bloodstream to the thyroid follicular cells in the first step and the rate-limiting step of thyroid hormonogenesis [11]. The carboxy-terminus of the protein, which is oriented toward the cytoplasm, contains specific sorting and retention signals required for NIS expression at the basolateral plasma membrane [12][13][14][15]. NIS-mediated active iodide transport is electrogenic and couples the inward translocation of one iodide ion against its electrochemical gradient to the inward transport of two sodium ions down its electrochemical gradient, generated by the sodium/potassium ATPase [16].…”