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CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation.
- Source :
-
Scientific reports [Sci Rep] 2018 Feb 22; Vol. 8 (1), pp. 3499. Date of Electronic Publication: 2018 Feb 22. - Publication Year :
- 2018
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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.
- Subjects :
- Adaptor Proteins, Signal Transducing
COP-Coated Vesicles genetics
COP-Coated Vesicles metabolism
Cullin Proteins genetics
Gene Expression Regulation genetics
Humans
Microfilament Proteins genetics
Myofibroblasts metabolism
Procollagen genetics
Receptor, Transforming Growth Factor-beta Type I genetics
Signal Transduction genetics
Transforming Growth Factor beta genetics
Ubiquitin-Protein Ligases genetics
Ubiquitination genetics
Chemokine CXCL12 genetics
Receptors, CXCR4 genetics
Transcriptional Activation genetics
Transcriptome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29472636
- Full Text :
- https://doi.org/10.1038/s41598-018-21506-7