Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
Biochim Biophys Acta Mol Basis Dis. 2020 May 1;1866(5):165723. doi: 10.1016/j.bbadis.2020.165723. Epub 2020 Feb 12.
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 (HO), 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.
衰老会引起细胞的形态和功能变化，同时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之一是 I 型胶原基因的下调。在本研究中，我们研究了肌球蛋白相关转录因子 A（MRTF-A）在这个过程中的作用。在小鼠胚胎成纤维细胞（MEF）和人包皮成纤维细胞（HFF）中，无论是通过连续传代还是过氧化氢（HO）处理诱导衰老，都会导致 MRTF-A 的赖氨酸乙酰化增加，同时 I 型胶原和去乙酰化酶 SIRT1 的表达下调。SIRT1 与 MRTF-A 相互作用，促进 MRTF-A 的去乙酰化。SIRT1 的过表达或选择性激动剂的激活增强了 MRTF-A 对胶原启动子的转录激活。相反，SIRT1 的耗竭或特异性拮抗剂的抑制抑制了 MRTF-A 对胶原启动子的转录激活。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 SIRT1 不敏感。重要的是，SIRT1 在衰老成纤维细胞中的激活减轻了 I 型胶原表达的抑制，而 SIRT1 的抑制则会促使年轻成纤维细胞过早失去 I 型胶原的表达。从机制上讲，SIRT1 增强了 MRTF-A 与 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，即 SIRT1 通过对 MRTF-A 的翻译后修饰，介导衰老相关的成纤维细胞中 I 型胶原的丢失。
