Deacetylation of MRTF-A by SIRT1 defies senescence induced down-regulation of collagen type I in fibroblast cells
Deacetylation of MRTF-A by SIRT1 defies senescence induced down-regulation of collagen type I in fibroblast cells
复制标题
SIRT1 对 MRTF-A 的去乙酰化可抵抗衰老诱导的成纤维细胞中 I 型胶原蛋白的下调
DOI：
10.1016/j.bbadis.2020.165723
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发表时间：
2020
影响因子：
6.2
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Yang Yuyu;Li Zilong;Guo Junli;Xu Yong
衰老引起细胞的形态和功能变化，伴随着基因表达模式的根本转变。与成纤维细胞衰老相关的特征性改变之一是I型胶原基因的下调。在本研究中，我们调查了心肌相关转录因子A，或MRTF-A，在这一过程中的贡献。在小鼠胚胎成纤维细胞（MEF）和人包皮成纤维细胞（HFF）细胞，衰老，诱导的渐进式通道或处理过氧化氢（H2 O2），导致增强赖氨酸乙酰化的MRTF-A平行下调I型胶原和SIRT 1，赖氨酸脱乙酰酶。SIRT 1与MRTF-A相互作用以促进MRTF-A的脱乙酰化。SIRT 1过表达或选择性激动剂激活增强了MRTF-A对胶原启动子的反式激活。相反，SIRT 1消耗或抑制特异性拮抗剂抑制MRTF-A的胶原启动子的反式激活。同样，MRTF-A中四个赖氨酸残基的突变使其在激活胶原启动子方面更有效，但对SIRT 1无反应。重要的是，衰老成纤维细胞中的SIRT 1激活减轻了I型胶原蛋白表达的抑制，而SIRT 1抑制促进了年轻成纤维细胞中I型胶原蛋白表达的过早丧失。从机制上讲，SIRT 1增强了MRTF-A对I型胶原启动子的亲和力。总之，我们的数据揭示了一种新的机制，强调通过SIRT 1介导的MRTF-A的翻译后修饰，成纤维细胞中I型胶原蛋白的老化相关损失。
Aging provokes both morphological and functional changes in cells, which are accompanied by a fundamental shift in gene expression patterns. One of the characteristic alterations associated with senescence in fibroblast cells is the down-regulation of collagen type I genes. In the present study, we investigated the contribution of myocardin-related transcription factor A, or MRTF-A, in this process. In mouse embryonic fibroblast (MEF) cells and human foreskin fibroblast (HFF) cells, senescence, induced by either progressive passage or treatment with hydrogen peroxide (H2O2), led to augmented lysine acetylation of MRTF-A paralleling down-regulation of collagen type I and SIRT1, a lysine deacetylase. SIRT1 interacted with MRTF-A to promote MRTF-A deacetylation. SIRT1 over-expression or activation by selective agonists enhanced trans-activation of the collagen promoters by MRTF-A. On the contrary, SIRT1 depletion or inhibition by specific antagonists suppressed trans-activation of the collagen promoters by MRTF-A. Likewise, mutation of four lysine residues within MRTF-A rendered it more potent in terms of activating the collagen promoters but unresponsive to SIRT1. Importantly, SIRT1 activation in senescent fibroblasts mitigated repression of collagen type I expression whereas SIRT1 inhibition promoted the loss of collagen type I expression prematurely in young fibroblasts. Mechanistically, SIRT1 enhanced the affinity of MRTF-A for the collagen type I promoters. In conclusion, our data unveil a novel mechanism that underscores aging-associated loss of collagen type I in fibroblasts via SIRT1-mediated post-translational modification of MRTF-A.