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The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes

A function-impairing mutation (feeble) or genomic deletion of SLC15A4 abolishes responses of nucleic acid–sensing endosomal toll-like receptors (TLRs) and significantly reduces disease in mouse models of lupus. Here, we demonstrate disease reduction in homozygous and even heterozygous Slc15a4 feeble...

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Autores principales: Rimann, Ivo, Gonzalez-Quintial, Rosana, Baccala, Roberto, Kiosses, William B., Teijaro, John R., Parker, Christopher G., Li, Xiaohong, Beutler, Bruce, Kono, Dwight H., Theofilopoulos, Argyrios N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169117/
https://www.ncbi.nlm.nih.gov/pubmed/35349343
http://dx.doi.org/10.1073/pnas.2200544119
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author Rimann, Ivo
Gonzalez-Quintial, Rosana
Baccala, Roberto
Kiosses, William B.
Teijaro, John R.
Parker, Christopher G.
Li, Xiaohong
Beutler, Bruce
Kono, Dwight H.
Theofilopoulos, Argyrios N.
author_facet Rimann, Ivo
Gonzalez-Quintial, Rosana
Baccala, Roberto
Kiosses, William B.
Teijaro, John R.
Parker, Christopher G.
Li, Xiaohong
Beutler, Bruce
Kono, Dwight H.
Theofilopoulos, Argyrios N.
author_sort Rimann, Ivo
collection PubMed
description A function-impairing mutation (feeble) or genomic deletion of SLC15A4 abolishes responses of nucleic acid–sensing endosomal toll-like receptors (TLRs) and significantly reduces disease in mouse models of lupus. Here, we demonstrate disease reduction in homozygous and even heterozygous Slc15a4 feeble mutant BXSB male mice with a Tlr7 gene duplication. In contrast to SLC15A4, a function-impairing mutation of SLC15A3 did not diminish type I interferon (IFN-I) production by TLR-activated plasmacytoid dendritic cells (pDCs), indicating divergence of function between these homologous SLC15 family members. Trafficking to endolysosomes and function of SLC15A4 were dependent on the Adaptor protein 3 (AP-3) complex. Importantly, SLC15A4 was required for trafficking and colocalization of nucleic acid–sensing TLRs and their ligands to endolysosomes and the formation of the LAMP2(+)VAMP3(+) hybrid compartment in which IFN-I production is initiated. Collectively, these findings define mechanistic processes by which SLC15A4 controls endosomal TLR function and suggest that pharmacologic intervention to curtail the function of this transporter may be a means to treat lupus and other endosomal TLR-dependent diseases.
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spelling pubmed-91691172022-06-07 The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes Rimann, Ivo Gonzalez-Quintial, Rosana Baccala, Roberto Kiosses, William B. Teijaro, John R. Parker, Christopher G. Li, Xiaohong Beutler, Bruce Kono, Dwight H. Theofilopoulos, Argyrios N. Proc Natl Acad Sci U S A Biological Sciences A function-impairing mutation (feeble) or genomic deletion of SLC15A4 abolishes responses of nucleic acid–sensing endosomal toll-like receptors (TLRs) and significantly reduces disease in mouse models of lupus. Here, we demonstrate disease reduction in homozygous and even heterozygous Slc15a4 feeble mutant BXSB male mice with a Tlr7 gene duplication. In contrast to SLC15A4, a function-impairing mutation of SLC15A3 did not diminish type I interferon (IFN-I) production by TLR-activated plasmacytoid dendritic cells (pDCs), indicating divergence of function between these homologous SLC15 family members. Trafficking to endolysosomes and function of SLC15A4 were dependent on the Adaptor protein 3 (AP-3) complex. Importantly, SLC15A4 was required for trafficking and colocalization of nucleic acid–sensing TLRs and their ligands to endolysosomes and the formation of the LAMP2(+)VAMP3(+) hybrid compartment in which IFN-I production is initiated. Collectively, these findings define mechanistic processes by which SLC15A4 controls endosomal TLR function and suggest that pharmacologic intervention to curtail the function of this transporter may be a means to treat lupus and other endosomal TLR-dependent diseases. National Academy of Sciences 2022-03-29 2022-04-05 /pmc/articles/PMC9169117/ /pubmed/35349343 http://dx.doi.org/10.1073/pnas.2200544119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Rimann, Ivo
Gonzalez-Quintial, Rosana
Baccala, Roberto
Kiosses, William B.
Teijaro, John R.
Parker, Christopher G.
Li, Xiaohong
Beutler, Bruce
Kono, Dwight H.
Theofilopoulos, Argyrios N.
The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes
title The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes
title_full The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes
title_fullStr The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes
title_full_unstemmed The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes
title_short The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes
title_sort solute carrier slc15a4 is required for optimal trafficking of nucleic acid–sensing tlrs and ligands to endolysosomes
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169117/
https://www.ncbi.nlm.nih.gov/pubmed/35349343
http://dx.doi.org/10.1073/pnas.2200544119
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