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

Scientific Reports
Susan C PatalanoJill A Macoska

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 ...Continue Reading

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Citations

Mar 16, 2019·Scientific Reports·Turgay SaritasJames A McCormick
Dec 14, 2018·Proceedings of the National Academy of Sciences of the United States of America·Lin YuanRandy Schekman
Mar 23, 2021·Frontiers in Veterinary Science·Julie BenningtonJ Koudy Williams

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Methods Mentioned

BETA
RNASeq
Ubiquitination
neddylation
RNA-Seq
Assay

Software Mentioned

EdgeR
GOstats
R
Cuffdiff
ClueGO
Cytoscape
ImageStudio
Illumina
Gen5
Bioconductor

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