A-kinase-anchoring protein-Lbc connects stress signaling to cardiac hypertrophy.
A-kinase-anchoring protein-Lbc connects stress signaling to cardiac hypertrophy.
复制标题
A-激酶锚定蛋白-Lbc 将应激信号传导与心脏肥大联系起来。
DOI：
10.1128/mcb.01490-12
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发表时间：
2013
影响因子：
5.3
通讯作者：
Scott,JohnD
中科院分区：
文献类型：
--
作者：
Smith,FDonelson;Scott,JohnD
心力衰竭通常是由于持续的心肌损伤而发生的。心血管疾病，包括高血压、瓣膜疾病、动脉粥样硬化和缺血，都可能导致压力超负荷和心肌功能障碍。面对这样的应激源，心脏试图通过启动一个复杂的重塑过程来维持正常的收缩功能，这一过程涉及发育基因的重新表达。这一过程导致心肌质量增加，通常被称为病理性心肌肥厚。如果创伤持续或严重，这种代偿机制就会不堪重负，或者变得不适应，从而导致心力衰竭。应激信号通路在细胞对心脏毒性损伤的反应中起着重要作用，如机械剪切和过多的促炎分子。此外，最近针对这些通路的有效药物治疗的发展重新引起了人们对应激信号在心肌细胞肥大中的作用的兴趣(1，2)。各种众所周知的信号级联反应是心肌细胞肥大发生的基础。尽管这些途径的确切分子细节尚不清楚，但几个研究小组已经发现了有价值的线索，表明导致这些表型的信号事件的复杂性(3)。肾上腺素能激动剂通过α1肾上腺素能受体(α1-AR)和Gα12激活小G蛋白RhoA，然后激活Jun N末端蛋白激酶和p38丝裂原活化蛋白激酶(MAPK)级联(4-6)。这些研究指出，压力信号是肥大反应的主要贡献者。描述肾上腺素能、小GTP酶和调节心脏重塑应激效应的细胞因子信号之间有趣的新联系(7)。Del Vescovo及其同事已经发现A-激酶锚定蛋白(AKAP)-LBC和I-κB激酶β(IKKβ)之间存在强大的蛋白质-蛋白质相互作用，IKK是核因子-κB信号的关键调节因子。有趣的是，AKAP-LBC是一种AKAP，它还具有Rho鸟嘌呤核苷酸交换因子(Global)活性，并作为参与心肌细胞功能的多种激酶的支架(5，8，9)。在此背景下，AKAP-LBC通过蛋白激酶D-组蛋白脱乙酰酶5途径促进胎儿基因重编程(10)，并作用于α1-肾上腺素能受体下游激活Gα12介导的RhoA信号转导(5)。通过质谱学和标准生化分析的结合，德尔·韦斯科沃和他的同事们证明了IKKβ与AKAP-LBC结合。这种应激激活的激酶将IκB磷酸化，并将其作为蛋白酶体降解的靶标，释放转录因子NF-κB，使其能够进入细胞核(11)。一旦进入细胞核，NF-κB就会启动预定的基因表达程序，以对抗心脏应激。更详细的生化图谱实验确定了AKAP-LBC Pleckstrin Homol末端有一个短螺旋区域-
Heart failure often occurs as a consequence of persistent trauma to the myocardium. Cardiovascular pathologies, including hypertension, valvular disease, atherosclerosis, and ischemia, can all lead to pressure overload and myocardial dysfunction. In the face of such stressors, the heart attempts to maintain normal contractile function by initiating a complex remodeling process involving the reexpression of developmental genes. This process leads to an increase in cardiac muscle mass commonly referred to as pathological cardiac hypertrophy. If trauma is persistent or severe, such compensatory mechanisms are overwhelmed or become maladaptive and heart failure ensues. Stress signaling pathways play an important role in cellular responses to cardiotoxic insults such as mechanical shear and an overabundance of proinflammatory molecules. Moreover, recent development of effective drug therapies targeting these pathways has renewed interest in the role of stress signaling in ventricular cardiomyocyte hypertrophy (1, 2). A variety of well-known signaling cascades underlie the onset of cardiomyocyte hypertrophy. Although the precise molecular details of these pathways are not clear, several groups have uncovered valuable clues that point to the complexity of the signaling events that lead to these phenotypes (3). Adrenergic agonists, acting through α1-adrenergic receptors (α1-AR) and Gα12, activate the small G protein RhoA, which then engages both the Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) kinase cascades (4–6). These studies point toward stress signaling as a major contributor to the hypertrophic response.In this issue, del Vescovo et al. describe an intriguing new connection between adrenergic, small GTPase, and cytokine signaling that regulates stress effects on cardiac remodeling (7). del Vescovo and colleagues have identified a robust protein-protein interaction between A-kinase-anchoring protein (AKAP)–Lbc and IκB kinase β (IKKβ), a crucial regulator of NF-κB signaling. Interestingly, AKAP-Lbc is an AKAP that also possesses Rho guanine nucleotide exchange factor (GEF) activity and acts as a scaffold for multiple kinases involved in cardiomyocyte function (5, 8, 9). In this context, AKAP-Lbc promotes fetal gene reprogramming through a protein kinase D (PKD)-histone deacetylase 5 (HDAC5) pathway (10) and functions downstream of α1-adrenergic receptors to activate Gα12-mediated RhoA signaling (5). Through a combination of mass spectrometry and standard biochemical analyses, del Vescovo and colleagues showed that IKKβ binds to AKAP-Lbc. This stress-activated kinase phosphorylates and targets IκB for proteasomal degradation, releasing the transcription factor NF-κB from inhibition and allowing it to enter the nucleus (11). Once in the nucleus, NF-κB initiates a predetermined program of gene expression to combat cardiac stresses. More-detailed biochemical mapping experiments identified a short helical region at the end of the AKAP-Lbc pleckstrin homol-