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The PDZ protein SCRIB regulates sodium/iodide symporter (NIS) expression at the basolateral plasma membrane.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Aug; Vol. 35 (8), pp. e21681. - Publication Year :
- 2021
-
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/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.<br /> (© 2021 Federation of American Societies for Experimental Biology.)
- Subjects :
- Amino Acid Sequence
Animals
Cell Line
Cell Membrane metabolism
Codon, Nonsense
Congenital Hypothyroidism genetics
Congenital Hypothyroidism metabolism
Conserved Sequence
Dogs
Endosomes metabolism
HEK293 Cells
Humans
Lysosomes metabolism
Madin Darby Canine Kidney Cells
Membrane Proteins chemistry
Membrane Proteins genetics
Models, Molecular
Mutagenesis, Site-Directed
PDZ Domains genetics
Protein Structure, Secondary
Rats
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Symporters chemistry
Symporters genetics
Thyroid Gland metabolism
Tumor Suppressor Proteins chemistry
Tumor Suppressor Proteins genetics
Membrane Proteins metabolism
Symporters metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 35
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 34196428
- Full Text :
- https://doi.org/10.1096/fj.202100303R