The misfolded myosin response in health and disease

健康和疾病中错误折叠的肌球蛋白反应

• 批准号: 417702515
• 负责人: Professor Dr. Steffen Just
• 金额: --
• 依托单位: Klinik für Innere Medizin II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/417702515?language=en
• 关键词: misfolded; myosin; response; health; disease

Myopathies are inherited, progressive diseases of heart and skeletal muscle that often lead to severe physical impairment and premature death of affected patients. Frequently, mutations in constituents of the basic contractile apparatus of striated muscle, the sarcomere, were found to be causative for disease onset and progression. Although the composition of the sarcomere is well known, the molecular regulation of its assembly and the interplay of auxiliary proteins such as Unc45b or Hsp90a that guarantee sarcomerogenesis are still incompletely understood. Unc45b and Hsp90a are known to specifically function to regulate myosin folding. Interestingly, animal models carrying loss-of-function mutations in these two myosin chaperones display massively disorganized muscle structures, myofilament disassembly and a severely impaired motility, substantiating the importance of auxiliary and regulatory proteins in the assembly of structural components into fully functional sarcomeres and myofilaments.Very recently, the methyltransferase SET- and MYND-domain-containing protein 1 (Smyd1) was identified as an interaction partner of Unc45b and Hsp90a but also muscle Myosin, suggesting that Smyd1, similar to or even together with Unc45b or Hsp90a, to be involved in the regulation of myosin folding and assembly in vivo. Mutation of Unc45b, Hsp90a or Smyd1b leads to the accumulation of misfolded myosin, the subsequent induction of a complex gene program termed the misfolded myosin response (MMR) and finally the impairment of myofibril formation during development.In the proposed research we now aim (1) to dissect the role of defined Smyd1 mutations (identified during the first funding period) and (2) of loss of Smyd1 on adult muscle function and structure. Furthermore, we aim (3) to identify Smyd1-specific non-histone methylation targets and their biological role in sarcomerogenesis and the misfolded myosin response. In addition to our analyses in zebrafish, we will (4) define the role of Smyd1 loss and the impact of human Smyd1 variants on development and function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Finally, we aim (5) to define and characterize factors, pathways and signaling networks (bioinformatics datasets) activated by the misfolded myosin response in vivo.In summary, the proposed research will ultimately help to further dissect the genetic and molecular underpinnings of sarcomere assembly and particularly myosin folding, which will be essential for the development of more specific strategies to treat diseases of striated muscle.

肌病是心脏和骨骼肌的遗传性、进行性疾病，通常导致严重的身体损害和受影响患者的过早死亡。通常，横纹肌的基本收缩装置，肌节的成分突变，被发现是疾病发作和进展的原因。虽然肌节的组成是众所周知的，但其组装的分子调控和辅助蛋白如Unc 45 b或Hsp 90 a的相互作用，保证肌节发生仍然不完全了解。Unc 45 b和Hsp 90 a是已知的特异性功能，以调节肌球蛋白折叠。有趣的是，在这两种肌球蛋白伴侣蛋白中携带功能丧失突变的动物模型显示出大量混乱的肌肉结构、肌丝分解和严重受损的运动性，证实了辅助和调节蛋白在将结构组分组装成完全功能的肌节和肌丝中的重要性。含有甲基转移酶SET-和MYND-结构域的蛋白1（Smyd 1）被鉴定为Unc 45 b和Hsp 90 a的相互作用配偶体，但也是肌肉肌球蛋白的相互作用配偶体，这表明Smyd 1与Unc 45 b或Hsp 90 a相似或甚至一起，参与体内肌球蛋白折叠和组装的调节。Unc 45 b、Hsp 90 a或Smyd 1b的突变导致错误折叠的肌球蛋白的积累，随后诱导一个复杂的基因程序，称为错误折叠肌球蛋白反应（MMR），最后在发育过程中损伤肌原纤维形成。在拟议的研究中，我们现在的目标是（1）剖析定义Smyd 1突变的作用，（在第一个资助期内确定）和（2）Smyd 1对成人肌肉功能和结构的损失。此外，我们的目标（3）确定Smyd 1特异性非组蛋白甲基化的目标和他们的生物学作用，在肌角化和错误折叠的肌球蛋白反应。除了我们在斑马鱼中的分析外，我们还将（4）确定Smyd 1丢失的作用以及人类Smyd 1变体对人类诱导多能干细胞衍生的心肌细胞（hiPSC-CM）发育和功能的影响。最后，我们的目标是（5）定义和表征体内错误折叠肌球蛋白反应激活的因子，途径和信号网络（生物信息学数据集）。总之，拟议的研究将最终有助于进一步剖析肌节组装，特别是肌球蛋白折叠的遗传和分子基础，这将是至关重要的发展更具体的战略，以治疗横纹肌疾病。