The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation
The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation
复制标题
免疫蛋白酶体催化 beta5i 亚基通过靶向自噬蛋白 ATG5 进行降解来调节心脏肥大。
DOI：
10.1126/sciadv.aau0495
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发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Li, Hui-Hua
中科院分区：
文献类型：
--
作者：
Xie, Xin;Bi, Hai-Lian;Li, Hui-Hua
病理性心脏肥大最终导致心力衰竭，如果没有适当的治疗。免疫蛋白酶体是蛋白酶体的诱导形式，其与炎性疾病密切相关。在这里，我们发现，免疫蛋白酶体催化亚基β 5i的表达和活性显着上调血管紧张素II（Ang II）处理的心肌细胞和肥大的心脏。在心肌细胞和小鼠中敲除β 5i显著减弱了肥大反应，并且在心肌细胞和转基因小鼠中过表达β 5i加重了这种作用。在机制上，β 5i与ATG 5相互作用并促进ATG 5降解，从而导致自噬和心脏肥大的抑制。此外，ATG5的敲除或自噬的抑制逆转了β 5i敲除介导的由Ang II或压力超负荷诱导的心肌细胞肥大的减少。总之，这项研究确定了β 5i在调节心脏肥大中的新作用。β 5i活性的抑制可能为肥大性疾病的治疗提供新的途径。
Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit beta 5i were significantly up-regulated in angiotensin II (Ang II)-treated cardiomyocytes and in the hypertrophic hearts. Knockout of beta 5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by beta 5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, beta 5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the beta 5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for beta 5i in the regulation of cardiac hypertrophy. The inhibition of beta 5i activity may provide a new therapeutic approach for hypertrophic diseases.