CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation.
CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation.
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DOI：
10.1038/s41598-018-21506-7
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发表时间：
2018-02-22
影响因子：
4.6
通讯作者：
Macoska J
中科院分区：
文献类型：
--
作者：
Patalano S;Rodríguez-Nieves J;Colaneri C;Cotellessa J;Almanza D;Zhilin-Roth A;Riley T;Macoska J
组织纤维化由多种促纤维化蛋白的作用介导，所述促纤维化蛋白可通过主要与Smads或MEK/Erk蛋白偶联的多种信号传导途径诱导肌成纤维细胞表型转化。TGFβ/TGFβR和CXCL 12/CXCR 4轴分别通过Smads和MEK/Erk蛋白独立地诱导肌成纤维细胞表型转化。为了在遗传水平上研究这些机制，我们现在已经阐明了人成纤维细胞中的TGFβ/TGFβR和CXCL 12/CXCR 4转录组。这些转录组在很大程度上是会聚的，并且上调编码已知促进肌成纤维细胞表型转化的蛋白质的转录物。这些研究还揭示了CXCL 12/CXCR 4轴激活COPII囊泡形成、泛素化和高尔基体/ER定位/靶向的独特分子特征。特别是，CUL 3和KLHL 12，参与前胶原从ER转运到高尔基体的Cullin-RING（CRL）泛素连接酶蛋白家族的关键成员，在CXCL 12-处理的细胞中高度上调，但在TGFβ-处理的细胞中受到抑制。CUL 3和KLHL 12的上调与CXCL 12处理的细胞的较高的前胶原分泌相关，并且这种影响在CXCR 4或CUL 3特异性抑制剂处理后被消除，并被TGFβ/TGFβR轴激活所抑制。这些研究的结果表明，CXCL 12/CXCR 4轴的激活通过COPII-囊泡介导的机制独特地促进前胶原I分泌，以促进纤维化特征性ECM的产生。
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.
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影响因子：
--
作者：
Hannah J;Zhou PB
通讯作者：
Zhou PB
影响因子：
64.8
作者：
Bashir, T;Dorrello, NV;Pagano, M
通讯作者：
Pagano, M
影响因子：
3.6
作者：
Dees, Clara;Chakraborty, Debomita;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J
影响因子：
3.8
作者：
Begley, L. A.;Kasina, S.;Macoska, J. A.
通讯作者：
Macoska, J. A.