Catalgol Betul, Ziaja Isabella, Breusing Nicolle, Jung Tobias, Höhn Annika, Alpertunga Buket, Schroeder Peter, Chondrogianni Niki, Gonos Efstathios S, Petropoulos Isabelle, Friguet Bertrand, Klotz Lars-Oliver, Krutmann Jean, Grune Tilman
Institute of Biological Chemistry and Nutrition, University of Hohenheim, 70593 Stuttgart, Germany.
J Biol Chem. 2009 Oct 30;284(44):30076-86. doi: 10.1074/jbc.M109.044503. Epub 2009 Aug 18.
Solar ultraviolet (UV) A radiation is a well known trigger of signaling responses in human skin fibroblasts. One important consequence of this stress response is the increased expression of matrix metalloproteinase-1 (MMP-1), which causes extracellular protein degradation and thereby contributes to photoaging of human skin. In the present study we identify the proteasome as an integral part of the UVA-induced, intracellular signaling cascade in human dermal fibroblasts. UVA-induced singlet oxygen formation was accompanied by protein oxidation, the cross-linking of oxidized proteins, and an inhibition of the proteasomal system. This proteasomal inhibition subsequently led to an accumulation of c-Jun and phosphorylated c-Jun and activation of activator protein-1, i.e. transcription factors known to control MMP-1 expression. Increased transcription factor activation was also observed if the proteasome was inhibited by cross-linked proteins or lactacystin, indicating a general mechanism. Most importantly, inhibition of the proteasome was of functional relevance for UVA-induced MMP-1 expression, because overexpression of the proteasome or the protein repair enzyme methionine sulfoxide reductase prevented the UVA-induced induction of MMP-1. These studies show that an environmentally relevant stimulus can trigger a signaling pathway, which links intracellular and extracellular protein degradation. They also identify the proteasome as an integral part of the UVA stress response.
日光紫外线A辐射是人类皮肤成纤维细胞信号反应的一种已知触发因素。这种应激反应的一个重要后果是基质金属蛋白酶-1（MMP-1）表达增加，这会导致细胞外蛋白质降解，从而促使人类皮肤光老化。在本研究中，我们确定蛋白酶体是紫外线A诱导的人类真皮成纤维细胞内信号级联反应的一个组成部分。紫外线A诱导的单线态氧形成伴随着蛋白质氧化、氧化蛋白质的交联以及蛋白酶体系统的抑制。这种蛋白酶体抑制随后导致c-Jun和磷酸化c-Jun的积累以及激活蛋白-1的激活，即已知控制MMP-1表达的转录因子。如果蛋白酶体被交联蛋白或乳胞素抑制，也会观察到转录因子激活增加，表明存在一种普遍机制。最重要的是，蛋白酶体抑制与紫外线A诱导的MMP-1表达具有功能相关性，因为蛋白酶体或蛋白质修复酶甲硫氨酸亚砜还原酶的过表达可防止紫外线A诱导的MMP-1诱导。这些研究表明，一种与环境相关的刺激可以触发一条信号通路，该通路将细胞内和细胞外蛋白质降解联系起来。它们还确定蛋白酶体是紫外线A应激反应的一个组成部分。
