Ubiquitin, a novel paracrine messenger of cardiac cell survival.
Ubiquitin, a novel paracrine messenger of cardiac cell survival.
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泛素，一种新型的心肌细胞存活的旁分泌信使。
DOI：
10.1093/cvr/cvq026
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发表时间：
2010
影响因子：
10.8
通讯作者：
Depre,Christophe
中科院分区：
文献类型：
--
作者：
Li,Dan;Depre,Christophe
泛素是一种高度保守且广泛表达的蛋白质，其通过赖氨酸（K）残基共价结合其它肽。传统上，泛素的作用与蛋白酶体的蛋白水解功能有关，称为泛素-蛋白酶体系统（UPS），负责约70 - 90%的细胞内蛋白质的降解。1，2在UPS中，泛素结合蛋白质被称为泛素化的过程中降解，并将它们转移到蛋白酶体进行蛋白水解。泛素化由泛素的C-末端羧基与靶蛋白的赖氨酸残基的1-氨基之间形成的肽键引起，并且这之后是多泛素链的合成，其中缀合的泛素（UbK48）的赖氨酸-48残基的1-氨基与引入的泛素部分的C-末端羧基结合。3靶蛋白的泛素化在很大程度上取决于E3泛素连接酶大家族的特定成员的身份，E3泛素连接酶催化泛素和客户端之间的肽键形成。4客户蛋白的多聚泛素化发出信号，其靶向蛋白酶体，用于由几种蛋白水解酶降解，这伴随着泛素单元的再循环。5 UPS的正常功能对于细胞内稳态至关重要，其功能障碍参与多种形式的疾病，包括心血管系统，最近在《聚焦》杂志上发表评论。6除了泛素在UPS中的这种"规范"功能之外，一个新兴的文献涉及泛素的"非规范"、蛋白酶体非依赖性和非蛋白水解活性，这些活性与DNA损伤和修复、细胞信号传导和运输以及转录控制等多种细胞功能有关。[7]泛素的这些非蛋白水解功能的一个显著特征是，它们涉及特异性E3连接酶的参与，该连接酶将泛素部分结合到赖氨酸63（UbK63）上，而不是赖氨酸-48上。[7]虽然UbK48和UbK63结合之间的差异乍一看似乎是轶事，但后者的过程产生了更线性的泛素部分链，这有利于它们与膜的相互作用，因为它们的疏水基序更好地暴露。8 Singh等9描述了泛素作为旁分泌剂抑制由β-肾上腺素能受体介导的心脏细胞凋亡的新功能。在这项研究中，作者观察到，刺激离体心肌细胞中的b1或b2肾上腺素能受体导致泛素在细胞外环境中的释放，随后被肌细胞重新摄取。作者还表明，细胞外环境中泛蛋白浓度的增加减弱了b-肾上腺素能受体刺激的促凋亡作用。该机制依赖于磷脂酰肌醇3-激酶（PI3K）/Akt途径的激活，导致GSK-3b和JNK的抑制，这两种信号传导机制促进线粒体凋亡途径的激活。9这一非常有趣的观察结果证实并进一步从机理上扩展了先前的体内报告，该报告描述了来自缺血猪心脏的泛素的细胞外产生。[10] Singh等人的这项研究为心脏中的泛素提供了一个新的角色，它是细胞存活的旁分泌信使，但它也提出了一些重要的问题。第一个问题是是否存在用于再摄取由心肌细胞产生的细胞外泛素的特异性受体和/或转运蛋白。这似乎是必需的，尽管肽的大小很小（约8kDa）。虽然这种可能性是从计算机实验中提出的，但它还没有...
Ubiquitin is a highly conserved and ubiquitously expressed protein that covalently binds other peptides by a lysine (K) residue. Traditionally, the role of ubiquitin is associated with the proteolytic function of the proteasome in what is known as the ubiquitin-proteasome system (UPS), responsible for the degradation of about 70–90% of intracellular proteins. 1, 2 In the UPS, ubiquitin binds the proteins to be degraded in a process known as ubiquitination and transfers them to the proteasome for proteolysis. Ubiquitination results from the formation of a peptide bond between the C-terminal carboxyl group of ubiquitin and the 1-amino group of a lysine residue of the target protein, and this is followed by the synthesis of a multi-ubiquitin chain in which the 1-amino group of the lysine-48 residue of the conjugated ubiquitin (UbK48) is bound to the C-terminal carboxyl group of the incoming ubiquitin moiety. 3 Ubiquitination of a target protein largely depends on the identity of specific members of the large family of E3 ubiquitin ligases, which catalyze the formation of the peptide bond between ubiquitin and the client. 4 Poly-ubiquitination of the client protein signals its targeting to the proteasome for degradation by several proteolytic enzymes, which is accompanied by the recycling of the ubiquitin units. 5 Proper function of the UPS is critical for cellular homeostasis, and its dysfunction participates in multiple forms of disease, including in the cardiovascular system, as reviewed recently in a Spotlight issue of the Journal. 6 Beside this ‘canonical’function of ubiquitin in the UPS, an emerging literature relates to ‘non-canonical’, proteasome-independent, and non-proteolytic activities of ubiquitin related to cellular functions as diverse as DNA damage and repair, cell signalling and trafficking, and transcriptional control. 7 A remarkable characteristic of these nonproteolytic functions of ubiquitin is that they involve the participation of specific E3 ligases conjugating the ubiquitin moiety not on lysine-48 but rather on lysine-63 (UbK63). 7 Although the difference between the UbK48 and UbK63 conjugation may seem anecdotic at first glance, the latter process produces a more linear chain of ubiquitin moieties, which favours their interaction with membranes due to a better exposure of their hydrophobic motifs. 8 Singh et al. 9 describe a novel function for ubiquitin as a paracrine agent to inhibit cardiac apoptosis mediated by b-adrenergic receptors. In this study, the authors observed that stimulation of b1 or b2 adrenergic receptors in isolated cardiac myocytes results in the release of ubiquitin in the extracellular milieu, followed by its reuptake in the myocytes. The authors also show that increased concentration of ubiquitin in the extracellular milieu blunts the pro-apoptotic effects of b-adrenergic receptor stimulation. The mechanism relies on an activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, resulting in the inhibition of GSK-3b and JNK, two signalling mechanisms that promote the activation of the mitochondrial pathway of apoptosis. 9 This very interesting observation confirms and further expands mechanistically a previous report in vivo describing an extracellular production of ubiquitin from the ischaemic swine heart. 10 This study by Singh et al. offers a new role for ubiquitin in the heart as a paracrine messenger of cell survival, but it also raises important questions. A first issue is whether there is a specific receptor and/or transporter for reuptake of the extracellular ubiquitin produced by the cardiomyocytes. This would seem required, despite the small size (about 8kDa) of the peptide. Although this possibility was suggested from experiments in silico, 11 it has not yet …