Loss of Collagen VII Is Associated with Reduced Transglutaminase 2 Abundance and Activity
Loss of Collagen VII Is Associated with Reduced Transglutaminase 2 Abundance and Activity
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DOI：
10.1038/jid.2014.185
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发表时间：
2014-09-01
影响因子：
6.5
通讯作者：
Dengjel, Joern
中科院分区：
文献类型：
--
作者：
Kuettner, Victoria;Mack, Claudia;Dengjel, Joern
胶原VII的缺乏导致广泛的细胞和组织表型。然而，其潜在的分子机制还不清楚。为了深入了解细胞对VII型胶原蛋白损失的反应，我们采用了定量疾病蛋白质组学方法。通过使用隐性营养不良性大疱性表皮病（RDEB），胶原蛋白VII缺乏引起的皮肤起泡疾病，作为遗传模型，胶原蛋白VII依赖的细胞蛋白丰度和蛋白质-蛋白质相互作用的差异进行了分析。胶原VII的缺乏导致细胞内蛋白质组成的改变和细胞粘附，蛋白质运输和周转途径自噬的扰动。不同细胞表型的潜在接头是转氨酶2（TGM 2），其是对蛋白质交联重要的多功能酶。TGM 2被鉴定为胶原VII的稳定相互作用伴侣。在RDEB中，TGM 2的丰度和活性都降低，这不仅是因为粘附减少和自噬紊乱，而且还因为细胞外基质交联减少和RDEB中表皮-真皮完整性降低。
Absence of collagen VII leads to widespread cellular and tissue phenotypes. However, the underlying molecular mechanisms are not well understood. To gain insights into cellular responses to loss of collagen VII, we undertook a quantitative disease proteomics approach. By using recessive dystrophic epidermolysis bullosa (RDEB), a skin blistering disease caused by collagen VII deficiency, as a genetic model, collagen VII-dependent differences in cellular protein abundances and protein-protein interactions were analyzed. Absence of collagen VII led to alterations of intracellular protein compositions and to perturbations in cell adhesion, protein trafficking, and the turnover pathway autophagy. A potential linker of the different cellular phenotypes is transglutaminase 2 (TGM2), a multifunctional enzyme important for protein cross-linking. TGM2 was identified as a stable interaction partner of collagen VII. In RDEB, both abundance and activity of TGM2 were reduced, accounting not only for diminished adhesion and perturbed autophagy but also for reduced cross-linking of the extracellular matrix and for decreased epidermal-dermal integrity in RDEB.