CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation

Abstract Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion indepen...

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Autores principales:	Susan Patalano, José Rodríguez-Nieves, Cory Colaneri, Justin Cotellessa, Diego Almanza, Alisa Zhilin-Roth, Todd Riley, Jill Macoska
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fcd37696a6fa47a0ac5b2a6efede8a62
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spelling	oai:doaj.org-article:fcd37696a6fa47a0ac5b2a6efede8a622021-12-02T12:32:21ZCXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation10.1038/s41598-018-21506-72045-2322https://doaj.org/article/fcd37696a6fa47a0ac5b2a6efede8a622018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21506-7https://doaj.org/toc/2045-2322Abstract Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion independently through Smads and MEK/Erk proteins, respectively. To investigate these mechanisms at the genetic level, we have now elucidated the TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human fibroblasts. These transcriptomes are largely convergent, and up-regulate transcripts encoding proteins known to promote myofibroblast phenoconversion. These studies also revealed a molecular signature unique to CXCL12/CXCR4 axis activation for COPII vesicle formation, ubiquitination, and Golgi/ER localization/targeting. In particular, both CUL3 and KLHL12, key members of the Cullin-RING (CRL) ubiquitin ligase family of proteins involved in procollagen transport from the ER to the Golgi, were highly up-regulated in CXCL12-, but repressed in TGFβ-, treated cells. Up-regulation of CUL3 and KLHL12 was correlated with higher procollagen secretion by CXCL12-treated cells, and this affect was ablated upon treatment with inhibitors specific for CXCR4 or CUL3 and repressed by TGFβ/TGFβR axis activation. The results of these studies show that activation of the CXCL12/CXCR4 axis uniquely facilitates procollagen I secretion through a COPII-vesicle mediated mechanism to promote production of the ECM characteristic of fibrosis.Susan PatalanoJosé Rodríguez-NievesCory ColaneriJustin CotellessaDiego AlmanzaAlisa Zhilin-RothTodd RileyJill MacoskaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Susan Patalano José Rodríguez-Nieves Cory Colaneri Justin Cotellessa Diego Almanza Alisa Zhilin-Roth Todd Riley Jill Macoska CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
description	Abstract Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion independently through Smads and MEK/Erk proteins, respectively. To investigate these mechanisms at the genetic level, we have now elucidated the TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human fibroblasts. These transcriptomes are largely convergent, and up-regulate transcripts encoding proteins known to promote myofibroblast phenoconversion. These studies also revealed a molecular signature unique to CXCL12/CXCR4 axis activation for COPII vesicle formation, ubiquitination, and Golgi/ER localization/targeting. In particular, both CUL3 and KLHL12, key members of the Cullin-RING (CRL) ubiquitin ligase family of proteins involved in procollagen transport from the ER to the Golgi, were highly up-regulated in CXCL12-, but repressed in TGFβ-, treated cells. Up-regulation of CUL3 and KLHL12 was correlated with higher procollagen secretion by CXCL12-treated cells, and this affect was ablated upon treatment with inhibitors specific for CXCR4 or CUL3 and repressed by TGFβ/TGFβR axis activation. The results of these studies show that activation of the CXCL12/CXCR4 axis uniquely facilitates procollagen I secretion through a COPII-vesicle mediated mechanism to promote production of the ECM characteristic of fibrosis.
format	article
author	Susan Patalano José Rodríguez-Nieves Cory Colaneri Justin Cotellessa Diego Almanza Alisa Zhilin-Roth Todd Riley Jill Macoska
author_facet	Susan Patalano José Rodríguez-Nieves Cory Colaneri Justin Cotellessa Diego Almanza Alisa Zhilin-Roth Todd Riley Jill Macoska
author_sort	Susan Patalano
title	CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
title_short	CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
title_full	CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
title_fullStr	CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
title_full_unstemmed	CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
title_sort	cxcl12/cxcr4-mediated procollagen secretion is coupled to cullin-ring ubiquitin ligase activation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/fcd37696a6fa47a0ac5b2a6efede8a62
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CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation

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