The UNC-45 chaperone is critical for establishing myosin-based myofibrillar organization and cardiac contractility in the Drosophila heart model.
The UNC-45 chaperone is critical for establishing myosin-based myofibrillar organization and cardiac contractility in the Drosophila heart model.
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DOI：
10.1371/journal.pone.0022579
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bernstein SI
中科院分区：
文献类型：
--
作者：
Melkani GC;Bodmer R;Ocorr K;Bernstein SI
UNC-45 is a UCS (UNC-45/CRO1/She4P) class chaperone necessary for myosin folding and/or accumulation, but its requirement for maintaining cardiac contractility has not been explored. Given the prevalence of myosin mutations in eliciting cardiomyopathy, chaperones like UNC-45 are likely to be equally critical in provoking or modulating myosin-associated cardiomyopathy. Here, we used the Drosophila heart model to examine its role in cardiac physiology, in conjunction with RNAi-mediated gene silencing specifically in the heart in vivo. Analysis of cardiac physiology was carried out using high-speed video recording in conjunction with movement analysis algorithms. unc-45 knockdown resulted in severely compromised cardiac function in adults as evidenced by prolonged diastolic and systolic intervals, and increased incidence of arrhythmias and extreme dilation; the latter was accompanied by a significant reduction in muscle contractility. Structural analysis showed reduced myofibrils, myofibrillar disarray, and greatly decreased cardiac myosin accumulation. Cardiac unc-45 silencing also dramatically reduced life-span. In contrast, third instar larval and young pupal hearts showed mild cardiac abnormalities, as severe cardiac defects only developed during metamorphosis. Furthermore, cardiac unc-45 silencing in the adult heart (after metamorphosis) led to less severe phenotypes. This suggests that UNC-45 is mostly required for myosin accumulation/folding during remodeling of the forming adult heart. The cardiac defects, myosin deficit and decreased life-span in flies upon heart-specific unc-45 knockdown were significantly rescued by UNC-45 over-expression. Our results are the first to demonstrate a cardiac-specific requirement of a chaperone in Drosophila, suggestive of a critical role of UNC-45 in cardiomyopathies, including those associated with unfolded proteins in the failing human heart. The dilated cardiomyopathy phenotype associated with UNC-45 deficiency is mimicked by myosin knockdown suggesting that UNC-45 plays a crucial role in stabilizing myosin and possibly preventing human cardiomyopathies associated with functional deficiencies of myosin.
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影响因子：
7.7
作者：
Amorim, Maria J.;Mata, Juan
通讯作者：
Mata, Juan
影响因子：
4
作者：
Lee, Chi F.;Melkani, Girish C.;Bernstein, Sanford I.
通讯作者：
Bernstein, Sanford I.
UNC-45伴侣通过秀丽隐杆线虫中的肌球蛋白降解介导了肌动蛋白降解。
影响因子：
7.8
作者：
Landsverk, Megan L;Li, Shumin;Hutagalung, Alex H;Najafov, Ayaz;Hoppe, Thorsten;Barral, Jose M;Epstein, Henry F
通讯作者：
Epstein, Henry F
影响因子：
56.9
作者：
Barral, JM;Hutagalung, AH;Epstein, HF
通讯作者：
Epstein, HF
影响因子：
--
作者：
Bernick EP;Zhang PJ;Du S
通讯作者：
Du S