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Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses

The molecular mechanisms that regulate late endosomal maturation and function are not completely elucidated, and direct evidence of a calcium sensor is lacking. Here we identify a novel mechanism of late endosomal maturation that involves a new molecular interaction between the tethering factor Munc...

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Autores principales: He, Jing, Johnson, Jennifer L., Monfregola, Jlenia, Ramadass, Mahalakshmi, Pestonjamasp, Kersi, Napolitano, Gennaro, Zhang, Jinzhong, Catz, Sergio D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751605/
https://www.ncbi.nlm.nih.gov/pubmed/26680738
http://dx.doi.org/10.1091/mbc.E15-05-0283
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author He, Jing
Johnson, Jennifer L.
Monfregola, Jlenia
Ramadass, Mahalakshmi
Pestonjamasp, Kersi
Napolitano, Gennaro
Zhang, Jinzhong
Catz, Sergio D.
author_facet He, Jing
Johnson, Jennifer L.
Monfregola, Jlenia
Ramadass, Mahalakshmi
Pestonjamasp, Kersi
Napolitano, Gennaro
Zhang, Jinzhong
Catz, Sergio D.
author_sort He, Jing
collection PubMed
description The molecular mechanisms that regulate late endosomal maturation and function are not completely elucidated, and direct evidence of a calcium sensor is lacking. Here we identify a novel mechanism of late endosomal maturation that involves a new molecular interaction between the tethering factor Munc13-4, syntaxin 7, and VAMP8. Munc13-4 binding to syntaxin 7 was significantly increased by calcium. Colocalization of Munc13-4 and syntaxin 7 at late endosomes was demonstrated by high-resolution and live-cell microscopy. Munc13-4–deficient cells show increased numbers of significantly enlarged late endosomes, a phenotype that was mimicked by the fusion inhibitor chloroquine in wild-type cells and rescued by expression of Munc13-4 but not by a syntaxin 7–binding–deficient mutant. Late endosomes from Munc13-4-KO neutrophils show decreased degradative capacity. Munc13-4–knockout neutrophils show impaired endosomal-initiated, TLR9-dependent signaling and deficient TLR9-specific CD11b up-regulation. Thus we present a novel mechanism of late endosomal maturation and propose that Munc13-4 regulates the late endocytic machinery and late endosomal–associated innate immune cellular functions.
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spelling pubmed-47516052016-04-16 Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses He, Jing Johnson, Jennifer L. Monfregola, Jlenia Ramadass, Mahalakshmi Pestonjamasp, Kersi Napolitano, Gennaro Zhang, Jinzhong Catz, Sergio D. Mol Biol Cell Articles The molecular mechanisms that regulate late endosomal maturation and function are not completely elucidated, and direct evidence of a calcium sensor is lacking. Here we identify a novel mechanism of late endosomal maturation that involves a new molecular interaction between the tethering factor Munc13-4, syntaxin 7, and VAMP8. Munc13-4 binding to syntaxin 7 was significantly increased by calcium. Colocalization of Munc13-4 and syntaxin 7 at late endosomes was demonstrated by high-resolution and live-cell microscopy. Munc13-4–deficient cells show increased numbers of significantly enlarged late endosomes, a phenotype that was mimicked by the fusion inhibitor chloroquine in wild-type cells and rescued by expression of Munc13-4 but not by a syntaxin 7–binding–deficient mutant. Late endosomes from Munc13-4-KO neutrophils show decreased degradative capacity. Munc13-4–knockout neutrophils show impaired endosomal-initiated, TLR9-dependent signaling and deficient TLR9-specific CD11b up-regulation. Thus we present a novel mechanism of late endosomal maturation and propose that Munc13-4 regulates the late endocytic machinery and late endosomal–associated innate immune cellular functions. The American Society for Cell Biology 2016-02-01 /pmc/articles/PMC4751605/ /pubmed/26680738 http://dx.doi.org/10.1091/mbc.E15-05-0283 Text en © 2016 He et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
He, Jing
Johnson, Jennifer L.
Monfregola, Jlenia
Ramadass, Mahalakshmi
Pestonjamasp, Kersi
Napolitano, Gennaro
Zhang, Jinzhong
Catz, Sergio D.
Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses
title Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses
title_full Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses
title_fullStr Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses
title_full_unstemmed Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses
title_short Munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and TLR9-initiated cellular responses
title_sort munc13-4 interacts with syntaxin 7 and regulates late endosomal maturation, endosomal signaling, and tlr9-initiated cellular responses
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751605/
https://www.ncbi.nlm.nih.gov/pubmed/26680738
http://dx.doi.org/10.1091/mbc.E15-05-0283
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