SUMO与乳腺癌

小泛素修饰物(Small ubiquitin-like modifier,SUMO)是结构上与泛素类似的一种修饰蛋白,能与一些特定的靶蛋白共价连接.与泛素介导蛋白质的降解不同,SUMO化修饰调控主要对靶蛋白的功能,如在蛋白质的稳定性、细胞定位、信号转导、基因转录调控等方面均发挥着重要的作用.最近的研究表明:SUMO与乳腺癌的发生发展密切相关,它是通过SUMO化修饰参与并影响雌激素受体信号通路来实现的,本文将就此做一综述.     

SUMO化在细胞生长中的作用

小泛素样修饰蛋白SUMO是与泛素相类似的蛋白质,属于类泛素蛋白家族中的一个重要成员。SUMO可参与蛋白质翻译后修饰,通过一系列酶介导的级联反应而共价结合于靶蛋白的赖氨酸残基上,该过程被称为SUMOylation,即SUMO化。近年来,继泛素在细胞中的作用被不断探索之后,SUMO蛋白的多种作用也被发掘而出。现就SUMO化在细胞周期、凋亡、信号通路与转录调控及细胞应激等方面的作用作一综述。     

蛋白质SUMO化修饰及其调控

SUMO化修饰是一种由SUMO特异性的活化酶(E1)、结合酶(E2)和连接酶(E3)共同催化完成的类泛素化修饰。同时,它又是一个动态且可逆的过程,介导去SUMO化的则是SUMO特异性蛋白酶(SENP)家族。SUMO化修饰的靶蛋白存在于细胞的各个部位,通过loss of function和gain of function机制,SUMO化修饰可调控蛋白质的活性与功能。SENPs介导的去SUMO化是决定靶蛋白SUMO化修饰水平的主要因素之一,同时SENPs也是调节蛋白SUMO化修饰的一个主要环节,因此SENPs在调控靶蛋白所参与的信号通路中发挥着重要作用。     

SUMO化修饰系统及其在肿瘤发展中的作用

小泛素相关修饰物(small ubiquitin-related modifier,SUMO)修饰是一种动态可逆的蛋白质翻译后修饰方式,SUMO蛋白可以共价结合到靶蛋白上。目前,在哺乳动物中,已经鉴定出4种不同的SUMO蛋白亚型,分别是SUMO-1、SUMO-2、SUMO-3和SUMO-4。SUMO化修饰对靶蛋白的功能具有重要的调节作用,如蛋白质的稳定性、亚细胞定位、信号转导、基因转录调控等。最新的研究表明,SUMO化修饰与肿瘤的发生、发展密切相关,但具体的机制还不清楚。该文就SUMO化修饰在肿瘤发展过程中作用机制的最新研究进展作一综述。     

泛素化和SUMO化对DEC1的拮抗调控作用

分化的胚软骨表达蛋白1(differentiated embryo-chondrocyte expressed gene 1,DEC1)作为一种时钟蛋白,除了在周期节律的调控中发挥转录抑制作用外,还在能量代谢以及多种肿瘤相关的信号通路的调控中发挥重要作用。此外,蛋白质的翻译后修饰是实现蛋白质功能精细调控的一种重要方式。目前发现,DEC1主要可被两种翻译后修饰,即泛素化和SUMO化修饰。尽管泛素化和SUMO化是两种过程非常类似的蛋白质翻译后修饰方式,但是它们对目的蛋白功能的调控却截然不同。由于泛素化和SUMO化与底物的作用靶点都是赖氨酸(Lys),因此在多数情况下,泛素化和SUMO化以拮抗性的方式调控底物蛋白的功能。鉴于此,该文旨在阐述泛素化和SUMO化修饰对DEC1功能的拮抗调节过程,为了解时钟蛋白DEC1对多种信号通路的调控过程中的分子机制提供新的思路。     

小泛素相关修饰物SUMO研究进展

蛋白质翻译后修饰对改变蛋白功能、活性或定位都起着非常重要的作用,泛素及其相似蛋白的修饰是其中一种重要形式。与其他诸如磷酸化、乙酰化、糖基化等不同的是,泛素及其相似蛋白的修饰基团本身即是一个小的多肽,通过异肽键与靶蛋白Lys侧链ε-NH2相连,其中小泛素相关修饰物(small ubiquitin—related modifier,SUMO)与蛋白的共价连接是一种新的广泛存在的翻译后修饰形式。SUMO是广泛存在于真核生物中高度保守的蛋白家族,在脊椎动物中有三个SUMO基因,称为SUMO-1,-2,-3,与泛素在二级结构上极其相似,且催化修饰过程的酶体系也具有很高的同源性。然而,与泛素化介导的蛋白酶降解途径不同,SUMO化修饰发挥着更为广泛的功能,如核质转运、细胞周期调控、信号转导、转录活性调控等。     

SENPs对肿瘤发展的分子调控机理

SUMO化修饰是一种把小泛素相关修饰物(small ubiquition related modifier,SUMO)共价连接到细胞内靶蛋白半胱氨酸残基上的一种蛋白质翻译后修饰。SUMO化修饰参与并调控着多种细胞进程,如转录调控、核转运和信号转导等。SUMO化修饰是一种动态可逆的修饰方式。SUMO特异性蛋白酶(SUMO-specific proteases,SENPs)可以使SUMO化修饰的蛋白质发生去SUMO化,在维持细胞内SUMO化与去SUMO化的平衡中起重要作用。研究表明,SENPs与多种癌症的发生发展密切相关,如SENP1能直接调节多条致癌通路,诱发正常的前列腺上皮细胞状态异常。癌细胞中的SENP3能诱导血管生成。因此,对去SUMO化机制研究可以为开发癌症治疗药物提供新的思路。     

SUMO化: 一种重要的体内翻译后蛋白质修饰系统

靶蛋白被小泛素相关修饰物(small ubiquitin-related modifier,SUMO)修饰已经成为真核细胞特有的翻译后蛋白质修饰标志之一.SUMO与靶蛋白之间这种可逆的共价连接,在核质运输、DNA与蛋白质结合活性、蛋白质之间相互作用、转录调控、DNA修复以及维持基因组稳定等方面均发挥着重要的调节作用.在许多人类疾病如癌症和神经退化性疾病中,SUMO化修饰作用对疾病的发生与发展起着极为重要的作用.阐明SUMO化修饰在这些疾病中的功能,将为疾病的治疗开辟一条崭新的思路.     

蛋白质多聚SUMO化修饰及其功能

泛素（ubiquitin, Ub）是一类高度保守的小蛋白, 可与靶蛋白的赖氨酸残基共价连接, 形成多聚泛素链行使功能. 类似于泛素化修饰过程, 小泛素相关修饰物(small ubiquitin related modifier, SUMO）也可以共价修饰靶蛋白的赖氨酸残基, 从而影响靶蛋白的定位、稳定性以及蛋白间的相互作用, 发挥重要的生理功能. 尽管在多数情况下, 靶蛋白发生的是单SUMO化修饰, 但最近研究发现,SUMO依赖自身的赖氨酸也可以形成多聚链. 与单SUMO化修饰不同的是, 多聚SUMO化修饰的靶蛋白可以进一步被泛素化修饰, 进而诱导靶蛋白的降解. 这是一种新的、特殊的化学修饰形式, 弄清它的生理功能,对于了解细胞的生长、分化以及凋亡等生理过程将具有重要的意义. 本文将就此方面的最新研究进展做一综述.     

SUMO化修饰在核受体功能调控中的作用

小泛素相关修饰蛋白(small ubiquitin related modifier,SUMO)修饰作用是蛋白质翻译后修饰的重要方式。SUMO化修饰与泛素化作用极为相似,并且在某些靶蛋白上可以与泛素竞争结合位点,从而起到稳定靶蛋白的作用,并参与调节靶蛋白的细胞定位、膜离子通道功能、DNA损伤修复以及转录活性等。核受体是一类在生物体内广泛分布的、配体依赖的转录因子超家族,参与机体生长发育、细胞分化,以及体内许多生理、病理过程中的基因表达调控。最近研究发现,核受体的SU-MO修饰可通过影响核受体的稳定性、转录活性、亚细胞定位等多重途径影响核受体的功能,并影响机体炎症反应及相关疾病的发生发展。本文对核受体的SUMO修饰在核受体功能调控中的作用,以及与机体相关疾病之间的关系做一简要综述。     

Emerging roles of the SUMO pathway in mitosis

SUMO proteins are small ubiquitin-like modifiers found in all eukaryotes that become covalently conjugated to other cellular proteins. The SUMO conjugation pathway is biochemically similar to ubiquitin conjugation, although the enzymes within the pathway act exclusively on SUMO proteins. This post-translational modification controls many processes. Here, I will focus on evidence that SUMOylation plays a critical role(s) in mitosis: Early studies showed a genetic requirement for SUMO pathway components in the process of cell division, while later findings implicated SUMOylation in the control of mitotic chromosome structure, cell cycle progression, kinetochore function and cytokinesis. Recent insights into the targets of SUMOylation are likely to be extremely helpful in understanding each of these aspects. Finally, growing evidence suggests that SUMOylation is a downstream target of regulation through Ran, a small GTPase with important functions in both interphase nuclear trafficking and mitotic spindle assembly.     

HIF-1α的可逆性SUMO化修饰

低氧诱导因子1(hypoxia inducible factor-1, HIF-1)是参与调节机体氧平衡的重要转录因子,在细胞低氧应答反应中起核心作用,能调节100多种涉及低氧应激下细胞适应和存活的靶基因．HIF-1由氧敏感的α亚基和在细胞内稳定表达的β亚基组成．其中α亚基可受到多种翻译后化学修饰作用,如在常氧下,HIF-1α通过泛素化蛋白酶修饰并导致其快速降解．最近几年发现的泛素样蛋白家族成员小泛素蛋白样修饰蛋白（SUMO）也能与HIF-1α共价结合．SUMO是一种分子量约为12 kD的小蛋白,从拟南芥到人类普遍存在．SUMO可共价结合许多靶底物蛋白,并对其进行翻译后修饰,该过程称为SUMO化．与泛素化蛋白酶体途径不同的是,SUMO化修饰能在常氧和相对低氧的条件下调节HIF-1α蛋白的稳定性,从而改变其转录活性．SUMO化是一个可逆的动态过程,可被特异性蛋白酶ULP/SENP将其从底物上去除．本文主要就HIF-1α的可逆性SUMO化修饰作一综述．     

Inducible SUMO modification of TANK alleviates its repression of TLR7 signalling

Adaptor proteins allow temporal and spatial coordination of signalling. In this study, we show SUMOylation of the adaptor protein TANK and its interacting kinase TANK‐binding kinase 1 (TBK1). Modification of TANK by the small ubiquitin‐related modifier (SUMO) at the evolutionarily conserved Lys 282 is triggered by the kinase activities of IκB kinase ε (IKKε) and TBK1. Stimulation of TLR7 leads to inducible SUMOylation of TANK, which in turn weakens the interaction with IKKε and thus relieves the negative function of TANK on signal propagation. Reconstitution experiments show that an absence of TANK SUMOylation impairs inducible expression of distinct TLR7‐dependent target genes, providing a molecular mechanism that allows the control of TANK function.     

HIF-1α的泛素化和SUMO化修饰

低氧诱导因子-1（hypoxia-inducible factor-1,HIF-1）是异二聚体的转录因子,由氧敏感的α亚基和在细胞内稳定表达的β亚基组成,在细胞低氧应答反应中起核心作用,能调节100多种涉及低氧应激下细胞适应和存活的靶基因.泛素是一种由76个氨基酸残基组成的保守性多肽,广泛存在真核生物中.SUMO是泛素样蛋白家族成员,分子量约为12 kD的小蛋白,从拟南芥到人类普遍存在.泛素和SUMO可共价结合许多靶底物蛋白,对其进行翻译后修饰,该过程分别称为泛素化与SUMO化.近来研究显示,HIF-1α的翻译后修饰如泛素化、SUMO化可调节其的稳定性,从而改变HIF 1α的转录激活活性.本文主要就HIF-1α泛素化及SUMO化修饰等问题作一综述.     

MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission

The modification of proteins by the small ubiquitin‐like modifier (SUMO) is known to regulate an increasing array of cellular processes. SUMOylation of the mitochondrial fission GTPase dynamin‐related protein 1 (DRP1) stimulates mitochondrial fission, suggesting that SUMOylation has an important function in mitochondrial dynamics. The conjugation of SUMO to its substrates requires a regulatory SUMO E3 ligase; however, so far, none has been functionally associated with the mitochondria. By using biochemical assays, overexpression and RNA interference experiments, we characterized the mitochondrial‐anchored protein ligase (MAPL) as the first mitochondrial‐anchored SUMO E3 ligase. Furthermore, we show that DRP1 is a substrate for MAPL, providing a direct link between MAPL and the fission machinery. Importantly, the large number of unidentified mitochondrial SUMO targets suggests a global role for SUMOylation in mitochondrial function, placing MAPL as a crucial component in the regulation of multiple conjugation events.     

Rapid identification of ubiquitination and SUMOylation target sites by microfluidic peptide array

SUMOylation and ubiquitination are two essential post translational modifications (PTMs) involved in the regulation of important biological processes in eukaryotic cells. Identification of ubiquitin (Ub) and small ubiquitin-related modifier (SUMO)-conjugated lysine residues in proteins is critical for understanding the role of ubiquitination and SUMOylation, but remains experimentally challenging. We have developed a powerful in vitro Ub/SUMO assay using a novel high density peptide array incorporated within a microfluidic device that allows rapid identification of ubiquitination and SUMOylation sites on target proteins. We performed the assay with a panel of human proteins and a microbial effector with known target sites for Ub or SUMO modifications, and determined that 80% of these proteins were modified by Ub or specific SUMO isoforms at the sites previously determined using conventional methods. Our results confirm the specificity for both SUMO isoform and individual target proteins at the peptide level. In summary, this microfluidic high density peptide array approach is a rapid screening assay to determine sites of Ub and SUMO modification of target substrates, which will provide new insights into the composition, selectivity and specificity of these PTM target sites.     

Molecular targets underlying SUMO‐mediated neuroprotection in brain ischemia

SUMOylation (small ubiquitin‐like modifier conjugation) is an important post‐translational modification which is becoming increasingly implicated in the altered protein dynamics associated with brain ischemia. The function of SUMOylation in cells undergoing ischemic stress and the identity of small ubiquitin‐like modifier (SUMO) targets remain in most cases unknown. However, the emerging consensus is that SUMOylation of certain proteins might be part of an endogenous neuroprotective response. This review brings together the current understanding of the underlying mechanisms and downstream effects of SUMOylation in brain ischemia, including processes such as autophagy, mitophagy and oxidative stress. We focus on recent advances and controversies regarding key central nervous system proteins, including those associated with the nucleus, cytoplasm and plasma membrane, such as glucose transporters (GLUT1, GLUT4), excitatory amino acid transporter 2 glutamate transporters, K⁺ channels (K2P1, K_v1.5, K_v2.1), GluK2 kainate receptors, mGluR8 glutamate receptors and CB1 cannabinoid receptors, which are reported to be SUMO‐modified. A discussion of the roles of these molecular targets for SUMOylation could play following an ischemic event, particularly with respect to their potential neuroprotective impact in brain ischemia, is proposed.