Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
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 |
_version_ | 1782415613630611456 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4751605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT hejing munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT johnsonjenniferl munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT monfregolajlenia munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT ramadassmahalakshmi munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT pestonjamaspkersi munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT napolitanogennaro munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT zhangjinzhong munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses AT catzsergiod munc134interactswithsyntaxin7andregulateslateendosomalmaturationendosomalsignalingandtlr9initiatedcellularresponses |