Combinatorial Omics Analysis Reveals Perturbed Lysosomal Homeostasis in Collagen VII-deficient Keratinocytes*
Combinatorial Omics Analysis Reveals Perturbed Lysosomal Homeostasis in Collagen VII-deficient Keratinocytes*
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组合组学分析揭示 VII 胶原蛋白缺乏的角质形成细胞中溶酶体稳态受到干扰*
DOI：
10.1074/mcp.ra117.000437
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发表时间：
2018
影响因子：
7
通讯作者：
Dengjel J
中科院分区：
文献类型：
--
作者：
Thriene K;Grüning BA;Bornert O;Erxleben A;Leppert J;Athanasiou I;Weber E;Kiritsi D;Nyström A;Reinheckel T;Backofen R;Bruckner-Tuderman L;Dengjel J
细胞外基质蛋白VI型胶原是复层上皮细胞微环境的一部分，在生物体内稳态中起关键作用。编码基因COL7A1的突变导致皮肤疾病营养不良性大疱性表皮松解症(DEB)，与皮肤脆性和进行性炎症驱动的纤维化有关，后者促进侵袭性皮肤癌。到目前为止，这些变化与间充质改变有关，VII型胶原丢失的上皮后果仍未得到充分解决。由于上皮功能障碍是纤维化的主要始发者，我们对DEB和对照组的原代人角质形成细胞进行了全面的转录组和蛋白质组分析，以生成与VII型胶原丢失相关的异常表皮分子通路的整体和详细图像。这些图像揭示了VII型胶原的相互作用伙伴在mRNA和蛋白质水平上的下调，但也增加了原代DEB角质形成细胞中S100促炎蛋白的丰度。VII型胶原缺失导致转化生长因子-β信号的增强与VII型胶原缺陷者角质形成细胞和皮肤中溶酶体蛋白水解酶活性增强有关。因此，失去一种单一的结构蛋白，即VII型胶原，会造成细胞外和细胞内的后果，导致炎症过程，使组织不稳定，并促进角质形成细胞驱动的进行性纤维化。
The extracellular matrix protein collagen VII is part of the microenvironment of stratified epithelia and critical in organismal homeostasis. Mutations in the encoding geneCOL7A1lead to the skin disorder dystrophic epidermolysis bullosa (DEB), are linked to skin fragility and progressive inflammation-driven fibrosis that facilitates aggressive skin cancer. So far, these changes have been linked to mesenchymal alterations, the epithelial consequences of collagen VII loss remaining under-addressed. As epithelial dysfunction is a principal initiator of fibrosis, we performed a comprehensive transcriptome and proteome profiling of primary human keratinocytes from DEB and control subjects to generate global and detailed images of dysregulated epidermal molecular pathways linked to loss of collagen VII. These revealed downregulation of interaction partners of collagen VII on mRNA and protein level, but also increased abundance of S100 pro-inflammatory proteins in primary DEB keratinocytes. Increased TGF-β signaling because of loss of collagen VII was associated with enhanced activity of lysosomal proteases in both keratinocytes and skin of collagen VII-deficient individuals. Thus, loss of a single structural protein, collagen VII, has extra- and intracellular consequences, resulting in inflammatory processes that enable tissue destabilization and promote keratinocyte-driven, progressive fibrosis.
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影响因子：
--
作者：
I. Vlodavsky
通讯作者：
I. Vlodavsky
影响因子：
11.2
作者：
Y. Ng;C. Pourreyron;J. Salas-Alanis;J. Dayal;R. Cepeda-Valdes;Wenfei Yan;S. Wright;Mei Chen;J. Fine;F. Hogg;J. McGrath;D. Murrell;I. Leigh;E. Lane;A. South
通讯作者：
Y. Ng;C. Pourreyron;J. Salas-Alanis;J. Dayal;R. Cepeda-Valdes;Wenfei Yan;S. Wright;Mei Chen;J. Fine;F. Hogg;J. McGrath;D. Murrell;I. Leigh;E. Lane;A. South
影响因子：
4.4
作者：
Eming, Sabine A.;Koch, Manuel;Fox, Jay W.
通讯作者：
Fox, Jay W.
影响因子：
--
作者：
Greenbaum, D;Medzihradszky, KF;Bogyo, M
通讯作者：
Bogyo, M
影响因子：
6.5
作者：
Kuettner, Victoria;Mack, Claudia;Dengjel, Joern
通讯作者：
Dengjel, Joern