Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Biol Chem. 2012 Nov 23;287(48):40513-24. doi: 10.1074/jbc.M112.404541. Epub 2012 Oct 9.
Mutations in LMNA gene cause cardiomyopathy, for which mechanistic insights are lacking.
Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy.
Dusp4 causes cardiac dysfunction and may contribute to the development of LMNA cardiomyopathy.
Revealing pathogenic mechanisms of LMNA cardiomyopathy is essential for the development of mechanism-based therapies. Mutations in the lamin A/C gene (LMNA) cause a diverse spectrum of diseases, the most common of which is dilated cardiomyopathy often with skeletal muscular dystrophy. Lamin A and C are fundamental components of the nuclear lamina, a dynamic meshwork of intermediate filaments lining the nuclear envelope inner membrane. Prevailing evidence suggests that the nuclear envelope functions as a signaling node and that abnormality in the nuclear lamina leads to dysregulated signaling pathways that underlie disease pathogenesis. We previously showed that activated ERK1/2 in hearts of a mouse model of LMNA cardiomyopathy (Lmna(H222P/H222P) mice) contributes to disease, but the complete molecular pathogenesis remains poorly understood. Here we uncover a pathogenic role of dual specificity phosphatase 4 (Dusp4), which is transcriptionally induced by ERK1/2. Dusp4 is highly expressed in the hearts of Lmna(H222P/H222P) mice, and transgenic mice with cardiac-selective overexpression of Dusp4 display heart dysfunction similar to LMNA cardiomyopathy. In both primary tissue and cell culture models, overexpression of Dusp4 positively regulates AKT-mTOR signaling, resulting in impaired autophagy. These findings identify a pathogenic role of Dusp4 in LMNA cardiomyopathy.
LMNA 基因突变会导致心肌病，但目前对此病的发病机制尚缺乏了解。
Dusp4 在 LMNA 心肌病的心脏中表达增强，其在小鼠中的过表达通过激活 AKT-mTOR 信号通路来实现，该信号通路会损害自噬。
Dusp4 导致心脏功能障碍，可能导致 LMNA 心肌病的发生。
揭示 LMNA 心肌病的发病机制对于开发基于机制的治疗方法至关重要。 lamin A/C 基因 (LMNA) 的突变会导致多种疾病，其中最常见的是扩张型心肌病，常伴有骨骼肌营养不良。 lamin A 和 C 是核层的基本组成部分，核层是一种动态的中间丝网格，位于核膜内膜的周围。现有的证据表明，核膜作为信号节点，核层的异常会导致失调的信号通路，从而导致疾病的发病机制。我们之前的研究表明，LMNA 心肌病（Lmna(H222P/H222P) 小鼠）模型心脏中的 ERK1/2 激活导致疾病，但完全的分子发病机制仍知之甚少。在这里，我们揭示了双特异性磷酸酶 4 (Dusp4) 的致病作用，Dusp4 由 ERK1/2 转录诱导。Dusp4 在 Lmna(H222P/H222P) 小鼠的心脏中高度表达，并且在心脏选择性过表达 Dusp4 的转基因小鼠中显示出与 LMNA 心肌病相似的心脏功能障碍。在原发性组织和细胞培养模型中，Dusp4 的过表达正向调节 AKT-mTOR 信号通路，导致自噬受损。这些发现确定了 Dusp4 在 LMNA 心肌病中的致病作用。
