A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter

Autores
Martín, Mariano; Modenutti, Carlos Pablo; Peyret, Victoria; Geysels, Romina Celeste; Darrouzet, Elisabeth; Pourcher, Thierry; Masini Repiso, Ana María; Marti, Marcelo Adrian; Carrasco, Nancy; Nicola, Juan Pablo
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The Na+/iodide (I2) symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I2 accumulation for thyroid hormonogenesis and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I2 transport than normal thyroid tissue (or even undetectable I2 transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane. Therefore, a thorough understanding of the mechanisms that regulate NIS plasma membrane transport would have multiple implications for radioiodide therapy. In this study, we show that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. Moreover, the carboxy-terminus contains dominant basolateral information. Using internal deletions and site-directed mutagenesis at the carboxy-terminus, we identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Furthermore, in clathrin adaptor protein (AP)-1B-deficient cells, NIS sorting to the basolateral plasma membrane is compromised, causing the protein to also be expressed at the apical plasma membrane. Computer simulations suggest that the AP-1B subunit s1 recognizes the monoleucine-based sorting motif in NIS carboxy-terminus. Although the mechanisms by which NIS is intracellularly retained in thyroid cancer remain elusive, our findings may open up avenues for identifying molecular targets that can be used to treat radioiodide-refractory thyroid tumors that express NIS intracellularly.
Fil: Martín, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Modenutti, Carlos Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Peyret, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina
Fil: Geysels, Romina Celeste. Universidad de Buenos Aires; Argentina
Fil: Darrouzet, Elisabeth. Université de Nice Sophia Antipolis-Université Côte d'Azur; Francia
Fil: Pourcher, Thierry. Université de Nice Sophia Antipolis-Université Côte d'Azur; Francia
Fil: Masini Repiso, Ana María. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Carrasco, Nancy. University of Yale; Estados Unidos
Fil: Nicola, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Materia
Endocrinology
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/128766
Acceder
id CONICETDig_8c2f98e694f958f4508a3ddc360115c3
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporterMartín, MarianoModenutti, Carlos PabloPeyret, VictoriaGeysels, Romina CelesteDarrouzet, ElisabethPourcher, ThierryMasini Repiso, Ana MaríaMarti, Marcelo AdrianCarrasco, NancyNicola, Juan PabloEndocrinologyhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The Na+/iodide (I2) symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I2 accumulation for thyroid hormonogenesis and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I2 transport than normal thyroid tissue (or even undetectable I2 transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane. Therefore, a thorough understanding of the mechanisms that regulate NIS plasma membrane transport would have multiple implications for radioiodide therapy. In this study, we show that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. Moreover, the carboxy-terminus contains dominant basolateral information. Using internal deletions and site-directed mutagenesis at the carboxy-terminus, we identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Furthermore, in clathrin adaptor protein (AP)-1B-deficient cells, NIS sorting to the basolateral plasma membrane is compromised, causing the protein to also be expressed at the apical plasma membrane. Computer simulations suggest that the AP-1B subunit s1 recognizes the monoleucine-based sorting motif in NIS carboxy-terminus. Although the mechanisms by which NIS is intracellularly retained in thyroid cancer remain elusive, our findings may open up avenues for identifying molecular targets that can be used to treat radioiodide-refractory thyroid tumors that express NIS intracellularly.Fil: Martín, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Modenutti, Carlos Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Peyret, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; ArgentinaFil: Geysels, Romina Celeste. Universidad de Buenos Aires; ArgentinaFil: Darrouzet, Elisabeth. Université de Nice Sophia Antipolis-Université Côte d'Azur; FranciaFil: Pourcher, Thierry. Université de Nice Sophia Antipolis-Université Côte d'Azur; FranciaFil: Masini Repiso, Ana María. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Carrasco, Nancy. University of Yale; Estados UnidosFil: Nicola, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaEndocrine Society2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/128766Martín, Mariano; Modenutti, Carlos Pablo; Peyret, Victoria; Geysels, Romina Celeste; Darrouzet, Elisabeth; et al.; A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter; Endocrine Society; Endocrinology; 160; 1; 1-2019; 156-1681945-7170CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/30496374/info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2018-00603info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:14:33Zoai:ri.conicet.gov.ar:11336/128766instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:14:33.993CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
title A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
spellingShingle A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
Martín, Mariano
Endocrinology
title_short A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
title_full A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
title_fullStr A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
title_full_unstemmed A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
title_sort A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter
dc.creator.none.fl_str_mv Martín, Mariano
Modenutti, Carlos Pablo
Peyret, Victoria
Geysels, Romina Celeste
Darrouzet, Elisabeth
Pourcher, Thierry
Masini Repiso, Ana María
Marti, Marcelo Adrian
Carrasco, Nancy
Nicola, Juan Pablo
author Martín, Mariano
author_facet Martín, Mariano
Modenutti, Carlos Pablo
Peyret, Victoria
Geysels, Romina Celeste
Darrouzet, Elisabeth
Pourcher, Thierry
Masini Repiso, Ana María
Marti, Marcelo Adrian
Carrasco, Nancy
Nicola, Juan Pablo
author_role author
author2 Modenutti, Carlos Pablo
Peyret, Victoria
Geysels, Romina Celeste
Darrouzet, Elisabeth
Pourcher, Thierry
Masini Repiso, Ana María
Marti, Marcelo Adrian
Carrasco, Nancy
Nicola, Juan Pablo
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Endocrinology
topic Endocrinology
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The Na+/iodide (I2) symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I2 accumulation for thyroid hormonogenesis and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I2 transport than normal thyroid tissue (or even undetectable I2 transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane. Therefore, a thorough understanding of the mechanisms that regulate NIS plasma membrane transport would have multiple implications for radioiodide therapy. In this study, we show that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. Moreover, the carboxy-terminus contains dominant basolateral information. Using internal deletions and site-directed mutagenesis at the carboxy-terminus, we identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Furthermore, in clathrin adaptor protein (AP)-1B-deficient cells, NIS sorting to the basolateral plasma membrane is compromised, causing the protein to also be expressed at the apical plasma membrane. Computer simulations suggest that the AP-1B subunit s1 recognizes the monoleucine-based sorting motif in NIS carboxy-terminus. Although the mechanisms by which NIS is intracellularly retained in thyroid cancer remain elusive, our findings may open up avenues for identifying molecular targets that can be used to treat radioiodide-refractory thyroid tumors that express NIS intracellularly.
Fil: Martín, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Modenutti, Carlos Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Peyret, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina
Fil: Geysels, Romina Celeste. Universidad de Buenos Aires; Argentina
Fil: Darrouzet, Elisabeth. Université de Nice Sophia Antipolis-Université Côte d'Azur; Francia
Fil: Pourcher, Thierry. Université de Nice Sophia Antipolis-Université Côte d'Azur; Francia
Fil: Masini Repiso, Ana María. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Carrasco, Nancy. University of Yale; Estados Unidos
Fil: Nicola, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
description The Na+/iodide (I2) symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I2 accumulation for thyroid hormonogenesis and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I2 transport than normal thyroid tissue (or even undetectable I2 transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane. Therefore, a thorough understanding of the mechanisms that regulate NIS plasma membrane transport would have multiple implications for radioiodide therapy. In this study, we show that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. Moreover, the carboxy-terminus contains dominant basolateral information. Using internal deletions and site-directed mutagenesis at the carboxy-terminus, we identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Furthermore, in clathrin adaptor protein (AP)-1B-deficient cells, NIS sorting to the basolateral plasma membrane is compromised, causing the protein to also be expressed at the apical plasma membrane. Computer simulations suggest that the AP-1B subunit s1 recognizes the monoleucine-based sorting motif in NIS carboxy-terminus. Although the mechanisms by which NIS is intracellularly retained in thyroid cancer remain elusive, our findings may open up avenues for identifying molecular targets that can be used to treat radioiodide-refractory thyroid tumors that express NIS intracellularly.
publishDate 2019
dc.date.none.fl_str_mv 2019-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/128766
Martín, Mariano; Modenutti, Carlos Pablo; Peyret, Victoria; Geysels, Romina Celeste; Darrouzet, Elisabeth; et al.; A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter; Endocrine Society; Endocrinology; 160; 1; 1-2019; 156-168
1945-7170
CONICET Digital
CONICET
url http://hdl.handle.net/11336/128766
identifier_str_mv Martín, Mariano; Modenutti, Carlos Pablo; Peyret, Victoria; Geysels, Romina Celeste; Darrouzet, Elisabeth; et al.; A carboxy-terminal monoleucine-based motif participates in the basolateral targeting of the Na+/I- symporter; Endocrine Society; Endocrinology; 160; 1; 1-2019; 156-168
1945-7170
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/30496374/
info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2018-00603
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Endocrine Society
publisher.none.fl_str_mv Endocrine Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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