p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction.
p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction.
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DOI：
10.1161/circresaha.111.254730
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发表时间：
2012-02-17
影响因子：
20.1
通讯作者：
Abe J
中科院分区：
文献类型：
--
作者：
Le NT;Takei Y;Shishido T;Woo CH;Chang E;Heo KS;Lee H;Lu Y;Morrell C;Oikawa M;McClain C;Wang X;Tournier C;Molina CA;Taunton J;Yan C;Fujiwara K;Patterson C;Yang J;Abe J
心肌细胞凋亡是心力衰竭发生、发展的关键事件之一，ICER（inducible cAMP early repressor）在此过程中的重要作用已有报道。已知ERK 5通过与CHIP泛素（Ub）连接酶结合并随后上调CHIP连接酶活性（其诱导ICER泛素化和随后的蛋白质降解）来抑制心肌梗死（MI）后的心脏细胞凋亡，特别是在高血糖状态下。ERK 5/CHIP相互作用的调控机制尚不清楚。我们先前证实了糖尿病心脏中p90 RSK激活增加。作为这项工作的逻辑延伸，我们现在研究p90 RSK激活是否抑制ERK 5介导的CHIP激活，并随后增加ICER水平和细胞凋亡。p90 RSK活化抑制ERK 5/CHIP缔合和CHIP Ub连接酶活性。p90 RSK和CHIP在ERK 5 C-末端结构域（aa 571 -807）中共享共同的结合位点。p90 RSK或ERK 5片段（aa 571 -807）的过表达抑制ERK 5/CHIP缔合，表明p90 RSK和CHIP竞争ERK 5结合，并且p90 RSK活化对于抑制ERK 5/CHIP相互作用至关重要。我们还鉴定了ERK 5-S496被p90 RSK直接磷酸化，并证明ERK 5-S496 A突变体显著损害血管紧张素II介导的CHIP活性抑制和随后的ICER水平增加。在体内，无论是心脏特异性耗竭ERK 5或p90 RSK的过度表达抑制CHIP活性，并加速心肌梗死后的心脏细胞凋亡-一种通过激活ERK 5完全可逆的现象。这些数据表明p90 RSK通过与ERK 5-S496结合和磷酸化在抑制CHIP活性和促进心脏凋亡中的作用。
Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent up-regulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown. We previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis. p90RSK activation inhibits ERK5/CHIP association and CHIP Ub ligase activity. p90RSK and CHIP share a common binding site in the ERK5 C-terminal domain (aa571-807). Overexpression of either p90RSK or an ERK5 fragment (aa571-807) inhibits ERK5/CHIP association, suggesting that p90RSK and CHIP competes for ERK5 binding and that p90RSK activation is critical for inhibiting ERK5/CHIP interaction. We also identified ERK5-S496 as being directly phosphorylated by p90RSK, and demonstrated that an ERK5-S496A mutant significantly impairs Angiotensin II-mediated inhibition of CHIP activity and subsequent increase in ICER levels. In vivo, either cardiac specific depletion of ERK5 or overexpression of p90RSK inhibits CHIP activity and accelerates cardiac apoptosis after MI--a phenomenon fully reversible by activating ERK5. These data suggest a role for p90RSK in inhibiting CHIP activity and promoting cardiac apoptosis through binding to and phosphorylation of ERK5-S496.