Department of Cardiovascular Internal Medicine, Jiangxi People's Hospital, Nanchang, 330006, China.
Department of Cardiovascular Internal Medicine, Jiangxi People's Hospital, Nanchang, 330006, China.
Exp Cell Res. 2020 Nov 1;396(1):112245. doi: 10.1016/j.yexcr.2020.112245. Epub 2020 Aug 31.
The constitutive photomorphogenic 9 (COP9) signalosome complex subunit 6 (COPS6/CSN6) is crucial for structural integrity of the COP9 signalosome complex. CSN6 participates in various aspects of cancer progression, but its role in hypertrophic cardiomyopathy is not clear. Here, we found that the expression of CSN6 was increased in Angiotensin II (Ang II)-induced hypertrophic mice hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of CSN6 decreased the cardiomyocyte size and fetal genes' expression in Ang II-induced hypertrophic NRCMs, while overexpression of CSN6 aggravated Ang II-induced myocardial hypertrophy. Moreover, we demonstrated that the pro-hypertrophic function of CSN6 was mediated by SIRT2, which acts as a cardioprotective factor in pathological cardiac hypertrophy. CSN6 inhibited the expression of SIRT2, and re-expression of SIRT2 attenuated the myocardial hypertrophy caused by CSN6 overexpression. Further investigation discovered that CSN6 suppressed the expression of SIRT2 via up-regulating Nkx2.2, a transcription suppressor of SIRT2. Mechanistically, CSN6 blocked the ubiquitin proteasome system-mediated degradation of Nkx2.2 protein by interacting with it and inhibiting its ubiquitination directly in cardiomyocytes. Finally, our data showed that CSN6 was partially dependent on the stabilization of Nkx2.2 protein to inhibit SIRT2 and promote myocardial hypertrophy. Overall, our study identified CSN6 as a pro-hypertrophic deubiquitinase, and CSN6 inhibition may be a potential treatment strategy for heart failure.
组成型光形态发生 9（COP9）信号体复合物亚基 6（COPS6/CSN6）对于 COP9 信号体复合物的结构完整性至关重要。CSN6 参与癌症进展的各个方面，但它在肥厚型心肌病中的作用尚不清楚。在这里，我们发现 CSN6 的表达在血管紧张素 II（Ang II）诱导的肥厚小鼠心脏和新生大鼠心肌细胞（NRCMs）中增加。CSN6 的抑制降低了 Ang II 诱导的肥厚 NRCMs 中的心肌细胞大小和胎儿基因的表达，而 CSN6 的过表达加重了 Ang II 诱导的心肌肥厚。此外，我们证明了 CSN6 的促肥厚功能是由 SIRT2 介导的，SIRT2 在病理性心肌肥厚中作为一种心脏保护因子发挥作用。CSN6 抑制了 SIRT2 的表达，而 SIRT2 的重新表达减轻了 CSN6 过表达引起的心肌肥厚。进一步的研究发现，CSN6 通过上调 SIRT2 的转录抑制因子 Nkx2.2 来抑制 SIRT2 的表达。在机制上，CSN6 通过与心肌细胞中的 Nkx2.2 蛋白相互作用并直接抑制其泛素化来阻止其泛素蛋白酶体系统介导的 Nkx2.2 蛋白降解。最后，我们的数据表明 CSN6 部分依赖于 Nkx2.2 蛋白的稳定来抑制 SIRT2 并促进心肌肥厚。总的来说，我们的研究确定了 CSN6 是一种促肥厚去泛素酶，CSN6 的抑制可能是心力衰竭的一种潜在治疗策略。
