Liu Yuting, Jiang Yajie, Ma Taiwei, Dong Wenjing, Yang Peng, Peng Lixia, Wang Baokun, Wu Chuanhong, Li Zhiqiang, Zhang Hong, Sun Yuanchao, Niu Yujuan, Ding Yonghe
The Affiliated Hospital of Qingdao University & Biomedical Sciences Institute, Qingdao Medical College of Qingdao University, Qingdao 266021, China.
Cardiovascular Surgery Department, Second Xiangya Hospital, Central South University, Changsha 410011, China.
Life Sci. 2025 Aug 1;374:123711. doi: 10.1016/j.lfs.2025.123711. Epub 2025 May 11.
Despite abundant expression of DNAJB6 gene in the heart, its roles in cardiac diseases remain underexplored. We aimed to investigate the function of its zebrafish (Danio rerio) ortholog, the dnajb6b gene, in cardiomyopathy and heart failure.
Both loss-of-function mutation and gain-of-function transgenic approaches were employed in zebrafish. High frequency echocardiography was performed to evaluate cardiac function indices in adult zebrafish. 4-phenylbutyric acid (4-PBA) was used to pharmacologically inhibit sarcoplasmic reticulum (SR) stress in zebrafish. Western blot was carried out to determine expression of DNAJB6 isoforms in human patients' heart tissues.
Global loss-of-function mutations affecting both the sarcomere-localized short (Dnajb6b[S]) and nucleus-localized long (Dnajb6b[L]) isoforms appeared phenotypically normal. In contrast, cardiomyocyte-specific overexpression of a truncated, sarcomere-localized Dnajb6b(L) isoform (Dnajb6b[∆L]) led to severe cardiomyopathy and heart failure phenotypes. Mechanistically, Dnajb6b responded to sarcoplasmic reticulum (SR) stress and activation of Dnajb6b(∆L) resulted in elevated SR stress, accumulation of ubiquitinated protein aggregation, and aberrant activation of autophagy. 4-PBA treatment partially rescued cardiac dysfunction and extended the lifespan of zebrafish with cardiomyocyte-specific activation of Dnajb6b(∆L). Finally, elevated expression of both DNAJB6(S) and DNAJB6(L) isoforms was detected in failing human hearts, supporting their clinical relevance.
Gain-of-function mutation in Dnajb6b(∆L) isoform causes cardiomyopathy and heart failure, likely mediated by elevated SR stress. This study enhances our understanding of Dnajb6's role in cardiac proteostasis and highlights its potential as a therapeutic target for the treatment of cardiomyopathy and heart failure.
尽管DNAJB6基因在心脏中大量表达，但其在心脏疾病中的作用仍未得到充分研究。我们旨在研究其斑马鱼直系同源基因dnajb6b在心肌病和心力衰竭中的功能。
在斑马鱼中采用功能丧失突变和功能获得转基因方法。使用高频超声心动图评估成年斑马鱼的心脏功能指标。用4-苯基丁酸（4-PBA）药理学抑制斑马鱼肌浆网（SR）应激。进行蛋白质免疫印迹法以确定人类患者心脏组织中DNAJB6亚型的表达。
影响肌节定位的短亚型（Dnajb6b[S]）和细胞核定位的长亚型（Dnajb6b[L]）的全功能丧失突变在表型上似乎正常。相比之下，截短的、肌节定位的Dnajb6b（L）亚型（Dnajb6b[∆L]）的心肌细胞特异性过表达导致严重的心肌病和心力衰竭表型。机制上，Dnajb6b对肌浆网（SR）应激有反应，Dnajb6b（∆L）的激活导致SR应激升高、泛素化蛋白聚集体积累和自噬异常激活。4-PBA处理部分挽救了心脏功能障碍，并延长了心肌细胞特异性激活Dnajb6b（∆L）的斑马鱼的寿命。最后，在衰竭的人类心脏中检测到DNAJB6（S）和DNAJB6（L）亚型的表达均升高，支持了它们的临床相关性。
Dnajb6b（∆L）亚型的功能获得突变导致心肌病和心力衰竭，可能由SR应激升高介导。本研究增进了我们对Dnajb6在心脏蛋白质稳态中的作用的理解，并突出了其作为心肌病和心力衰竭治疗靶点的潜力。
