Melkani Girish C, Bhide Shruti, Han Andrew, Vyas Jay, Livelo Catherine, Bodmer Rolf, Bernstein Sanford I
Department of Biology, Molecular Biology and Heart Institutes, San Diego State University, CA, USA.
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
FEBS Lett. 2017 Nov;591(21):3447-3458. doi: 10.1002/1873-3468.12860. Epub 2017 Oct 10.
We recently reported that CCT chaperonin subunits are upregulated in a cardiac-specific manner under time-restricted feeding (TRF) [Gill S et al. (2015) Science 347, 1265-1269], suggesting that TRiC/CCT has a heart-specific function. To understand the CCT chaperonin function in cardiomyocytes, we performed its cardiac-specific knock-down in the Drosophila melanogaster model. This resulted in disorganization of cardiac actin- and myosin-containing myofibrils and severe physiological dysfunction, including restricted heart diameters, elevated cardiac dysrhythmia and compromised cardiac performance. We also noted that cardiac-specific knock-down of CCT chaperonin significantly shortens lifespans. Additionally, disruption of circadian rhythm yields further deterioration of cardiac function of hypomorphic CCT mutants. Our analysis reveals that both the orchestration of protein folding and circadian rhythms mediated by CCT chaperonin are critical for maintaining heart contractility.
我们最近报道，在限时喂养（TRF）条件下，CCT伴侣蛋白亚基以心脏特异性方式上调[吉尔·S等人（2015年）《科学》347卷，1265 - 1269页]，这表明TRiC/CCT具有心脏特异性功能。为了解CCT伴侣蛋白在心肌细胞中的功能，我们在果蝇模型中对其进行了心脏特异性敲低。这导致含有心脏肌动蛋白和肌球蛋白的肌原纤维紊乱以及严重的生理功能障碍，包括心脏直径受限、心律失常增加和心脏功能受损。我们还注意到，CCT伴侣蛋白的心脏特异性敲低显著缩短了寿命。此外，昼夜节律的破坏会使低表达CCT突变体的心脏功能进一步恶化。我们的分析表明，由CCT伴侣蛋白介导的蛋白质折叠编排和昼夜节律对于维持心脏收缩力都至关重要。
