铁代谢与蛋白质泛素化．降解调控研究进展

铁元素为几乎所有的生命体所必需,维持铁代谢稳态对机体的正常功能至关重要。铁代谢紊乱与人类多种疾病的发生和发展有关。已知铁代谢稳态受到一系列参与铁代谢环节的关键蛋白质,如IRP2等的精确调节。这些重要蛋白质的稳定性、生理活性的动态变化及其协调作用是细胞维持铁代谢平衡的分子基础。除了转录和转录后水平的调控,泛素化等翻译后修饰方式和蛋白质降解是细胞精确调控参与铁代谢的蛋白质的水平及功能普遍而有效的方式之一;同时,细胞的铁代谢状态也影响细胞内参与泛素化等翻译后修饰途径的酶类的活性和稳定性,从而在铁代谢和蛋白质修饰．降解途径之间形成反馈机制,实时和动态地完成对细胞内铁代谢水平的精确调控。就相关领域的最新进展作简要综述。     

赖氨酸乙酰化调控细胞代谢的机制

赖氨酸乙酰化是一种重要的翻译后修饰。细胞内的蛋白质,特别是代谢酶,广泛受乙酰化修饰的调控。乙酰化修饰由乙酰化酶和去乙酰化酶调节,对细胞的物质代谢和能量稳态进行多层次、复杂而又精细的调控。乙酰化酶和去乙酰化酶活性的发挥依赖中间代谢产物,且多种代谢物能够调控乙酰化酶和去乙酰化酶的催化活力。因此,乙酰化修饰是调控细胞代谢的重要机制。此外,乙酰化修饰能够调节自噬和营养物质感受通路,从而调控细胞的物质和能量稳态;乙酰化修饰对组蛋白的调节则能根据细胞的营养状态在表观遗传水平改变基因的表达,使细胞高效地应对不同的营养和压力状态。乙酰化修饰与代谢相关疾病的发生发展具有重要联系,对乙酰化调控的研究将极大增进人们对细胞代谢、表观遗传等生命活动的认识。     

蓝藻的蛋白质翻译后修饰研究进展

蛋白质翻译后修饰系统几乎参与了细胞所有的正常生命活动过程,并发挥着重要的调控作用。目前,基于生物质谱技术进行蛋白质翻译后修饰的规模化分析鉴定,已经成为蛋白质组学研究的核心内容之一。近年来的研究表明,蓝藻细胞中存在着复杂的蛋白质翻译后修饰系统,如磷酸化,乙酰化,甲基化,糖基化,氧化等,这些翻译后修饰在蓝藻细胞的代谢过程中可能发挥着重要的调控作用。本文主要针对蓝藻细胞中蛋白质翻译后修饰的发现与鉴定,以及翻译后修饰潜在的生物学功能展开简要综述。     

细胞代谢过程中的酶促糖基化及其功能

细胞代谢过程中多样的生化修饰反应能够精细调控细胞的活力与功能。其中,酶促糖基化是细胞代谢调控过程中普遍存在的一种分子修饰,对维持和调节细胞功能具有重要影响。糖基转移酶通过将糖基供体的糖基转移至相应的受体分子来实现糖基化修饰。受体分子经过糖基化修饰会改变其在细胞内的稳定性、溶解性和区域定位等特性,并在调节细胞周期、信号转导、蛋白质表达调控、应答反应和清除细胞异物等诸多生物过程中起着重要作用。简要介绍了细胞代谢过程中糖基转移酶超家族的分类、命名和催化机制。重点阐述细胞中蛋白质类生物大分子和小分子化合物的糖基化反应及其在细胞代谢过程中的功能。展望了细胞中糖基化反应及糖基转移酶在人类健康、医药产品、工业催化、食品和农业等领域的应用前景。     

蛋白质SUMO化修饰与肿瘤调控

SUMO化修饰是一种重要的蛋白质翻译后修饰方式,在细胞周期调控、细胞代谢、基因转录、DNA损伤和修复等众多细胞生物学过程中,对底物蛋白质的表达、定位和活性进行调控。蛋白质SUMO化修饰是动态可逆的过程,去SUMO化修饰由SUMO特异性蛋白酶(SENPs)家族成员所催化。由于受到SUMO化修饰的底物蛋白种类众多、功能多样,SUMO化修饰能够在整体和特定蛋白质修饰层面,参与调控肿瘤的发生发展,并且这种调控机制非常复杂,比如调控细胞周期的进程、DNA损伤和基因组不稳定性、肿瘤代谢与生长、抗肿瘤免疫等。SENPs家族成员是底物蛋白质SUMO化修饰程度的决定者,该研究团队对SENPs家族成员在肿瘤中的作用开展了系列研究,因此该文也将以SENP1和SENP3为例,对SENPs在肿瘤进程中的作用及其作用机制展开介绍。     

转录因子的巯基亚硝基化修饰及其生理学意义

巯基亚硝基化(S-nitrosylation)修饰是一种一氧化氮(nitric oxide, NO)介导的氧化还原依赖的、可逆性蛋白质翻译后修饰。生理条件下,S-nitrosylation通过调控蛋白质的稳定性、蛋白质活性、亚细胞定位及蛋白质-蛋白质相互作用,在维持细胞稳态中发挥重要作用。而在多种病理条件下,蛋白质S-nitrosylation及其产物表现出异常的升高或降低。转录因子又称反式作用因子,通过识别并结合调控元件而影响基因转录。本文简要综述转录因子的S-nitrosylation修饰的研究进展及其生理学意义。     

蛋白质的翻译后修饰与肿瘤代谢

蛋白质的翻译后修饰(post-translational modifications, PTMs)可改变蛋白质的稳定性、活性或细胞定位,是其功能调控的重要方式。常见的修饰类型包括赖氨酸残基上的乙酰化、泛素化、甲基化以及丝氨酸/苏氨酸残基上的磷酸化、糖基化修饰等。研究发现蛋白质的PTMs与肿瘤的代谢及生长密切相关,而靶向蛋白质PTMs与肿瘤代谢调控的治疗策略或将具有良好的临床应用前景。本文将对蛋白质的PTMs与肿瘤代谢及生长调控间相互作用的研究进展做一阐述。     

翻译后修饰对转录因子NF-E2相关因子2功能的调控

抗氧化反应组件（AREs）普遍存在于编码抗氧化和/或解毒酶基因的启动子区域,为这些基因的转录启动所必需;而这些基因的表达对维持细胞内氧化还原稳态,抵抗活性氧类（ROS）引起的细胞损伤发挥重要作用。转录因子NF E2相关因子2(nuclear factor erythroid 2 related factor 2, NRF2)作为抗氧化反应中的关键转录因子,可以与ARE结合,启动其下游靶基因,在氧化应激及亲电子剂应激中发挥重要的调控作用,广泛参与炎症、增殖、凋亡、细胞分化、组织再生和代谢等过程;因此,激活NRF2有望成为治疗肿瘤及其他与氧化、炎症相关疾病的新策略。蛋白质的翻译后修饰,对蛋白质空间构象、稳定性及其与其他蛋白质间相互作用具有重要作用。因此,探究NRF2的翻译后修饰如磷酸化、乙酰化和泛素化的修饰过程等,对深入了解NRF2的功能及调控机制至关重要,并与某些疾病的发生发展密切相关。本文对近年来翻译后修饰对NRF2的活性及功能的调控进行综述。     

氨基酸调控肝脏糖脂代谢的作用与机制

氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接各种组织代谢的枢纽。氨基酸感应在肝脏糖脂代谢的调控中起到十分重要的作用。因此准确地感应细胞内和细胞外氨基酸的水平,成为维持细胞内稳态的关键。真核细胞中存在一些众所周知的氨基酸感应因子,即一般性调控阻遏蛋白激酶2 (general control non-derepressible-2, GCN2)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)以及味觉受体等,在维持机体代谢稳态中发挥重要作用。本文对氨基酸调控肝脏糖脂代谢的作用与机制做了详细介绍,为进一步探究氨基酸感应机制以及治疗肝脏糖脂代谢紊乱疾病奠定了基础。     

RNA结合蛋白在多能干细胞命运转变中的研究进展

RNA结合蛋白(RNA binding proteins,RBPs)是一类通过其RNA结合结构域与RNA相互作用的蛋白质,在细胞内发挥着非常重要的作用。RBPs参与从RNA代谢(包括RNA的可变剪接、稳定性、翻译)到表观遗传修饰等多种调控途径。已有大量文献报道转录因子、表观遗传修饰和细胞外信号通路参与调控干细胞的多能性维持、分化和体细胞重编程,但对于RBPs在细胞命运转变中作用的研究报道甚少。该文主要综述了RBPs通过调控RNA的可变剪接、mRNA稳定性、翻译水平、microRNA代谢及组蛋白修饰进而调控干细胞多能性维持和体细胞重编程。     

The sulfur formation system mediating extracellular cysteine-cystine recycling in Fervidobacterium islandicum AW-1 is associated with keratin degradation

Most extremophilic anaerobes possess a sulfur formation (Suf) system for Fe–S cluster biogenesis. In addition to its essential role in redox chemistry and stress responses of Fe–S cluster proteins, the Suf system may play an important role in keratin degradation by Fervidobacterium islandicum AW-1. Comparative genomics of the order Thermotogales revealed that the feather-degrading F. islandicum AW-1 has a complete Suf-like machinery (SufCBDSU) that is highly expressed in cells grown on native feathers in the absence of elemental sulfur (S⁰). On the other hand, F. islandicum AW-1 exhibited a significant retardation in the Suf system-mediated keratin degradation in the presence of S⁰. Detailed differential expression analysis of sulfur assimilation machineries unveiled the mechanism by which an efficient sulfur delivery from persulfurated SufS to SufU is achieved during keratinolysis under sulfur starvation. Indeed, addition of SufS–SufU to cell extracts containing keratinolytic proteases accelerated keratin decomposition in vitro under reducing conditions. Remarkably, mass spectrometric analysis of extracellular and intracellular levels of amino acids suggested that redox homeostasis within cells coupled to extracellular cysteine and cystine recycling might be a prerequisite for keratinolysis. Taken together, these results suggest that the Suf-like machinery including the SufS–SufU complex may contribute to sulfur availability for an extracellular reducing environment as well as intracellular redox homeostasis through cysteine released from keratin hydrolysate under starvation conditions.     

The role of sulfur assimilation and sulfur-containing compounds in trace element homeostasis in plants

Sulfur assimilation and production of sulfur-containing compounds are essential biological activities that play critical roles in many biological processes, including the role of sulfur containing compounds such as glutathione and phytochelatin in trace element homeostasis in plants. This review will discuss the role of sulfur assimilation and the biosynthesis of sulfur containing compounds in both mechanisms of trace element hyperaccumulation and heavy metal stress responses in plants.     

Sulfide is an efficient iron releasing agent for mammalian ferritins

The most prominent role of mammalian ferritins is to provide an extensive iron-buffering capacity to cells. The large ferritin iron stores can be mobilized in vitro, but the functional relevance of the most efficient iron releasing agents remains elusive. Sulfide is a strongly reducing chemical generated by a series of enzymes. In the presence of limited amounts of sulfide a continuous rate of iron release from ferritin was observed and a majority of the protein iron core was recovered in solution. The rate constants for iron efflux triggered by several reducing or chelating compounds have been measured and compared. Although not as efficient as reduced flavins, sulfide displayed kinetic parameters which suggest a potential physiological role for the chalcogenide in converting the iron storage protein into apoferritin. To further probe the relevance of sulfide in the mobilization of iron, several enzymes, such as NifS, rhodanese, or sulfite reductase generating reduced forms of sulfur by different mechanisms, have been assayed for their ability to catalyze the release of iron from ferritin. The results show that full reduction of sulfur into sulfide is needed to deplete iron from ferritin. These reactions suggest links between sulfur metabolism and intracellular iron homeostasis.     

Cellular and mitochondrial iron homeostasis in vertebrates

Iron plays an essential role in cellular metabolism and biological processes. However, due to its intrinsic redox activity, free iron is a potentially toxic molecule in cellular biochemistry. Thus, organisms have developed sophisticated ways to import, sequester, and utilize iron. The transferrin cycle is a well-studied iron uptake pathway that is important for most vertebrate cells. Circulating iron can also be imported into cells by mechanisms that are independent of transferrin. Once imported into erythroid cells, iron is predominantly consumed by the mitochondria for the biosynthesis of heme and iron sulfur clusters. This review focuses on canonical transferrin-mediated and the newly discovered, non-transferrin mediated iron uptake pathways, as well as, mitochondrial iron homeostasis in higher eukaryotes. This article is part of a Special Issue entitled: Cell Biology of Metals.     

Allyl sulfur compounds and cellular detoxification system: effects and perspectives in cancer therapy

Natural organosulfur compounds (OSCs) have been shown to have chemopreventive effects and to suppress the proliferation of tumor cells in vitro through the induction of apoptosis. The biochemical mechanisms underlying the antitumorigenic and anti-proliferative effects of garlic-derived OSCs are not fully understood. Several modes of action of these compounds have been proposed, and it seems likely that the rate of clearance of allyl sulfur groups from cells is a determinant of the overall response. The aim of this review is to focus attention on the effects of natural allyl sulfur compounds on the cell detoxification system in normal and tumor cells. It has been already reported that several natural allyl sulfur compounds induce chemopreventive effects by affecting xenobiotic metabolizing enzymes and inducing their down-activation. Moreover, different effects of water- and oil-soluble allyl sulfur compounds on enzymes involved in the detoxification system of rat tissues have been observed. A direct interaction of the garlic allyl sulfur compounds with proteins involved in the detoxification system was studied in order to support the hypothesis that proteins possessing reactive thiol groups and that are involved in the detoxification system and in the cellular redox homeostasis, are likely the preferential targets of these compounds. The biochemical transformation of the OSCs in the cell and their adducts with thiol functional groups of these proteins, could be considered relevant events to uncover the anticancer properties of the allyl sulfur compounds. Although additional studies, using proteomic approaches and transgenic models, are needed to identify the molecular targets and modes of action of these natural compounds, the allyl sulfur compounds can represent potential ideal agents in anticancer therapy, either alone or in association with other antitumor drugs.     

Metallothionein redox cycle and function

The biologic function of metallothionein (MT) has been a perplexing topic ever since the discovery of this protein. Many studies have suggested that MT plays a role in the homeostasis of essential metals such as zinc and copper, detoxification of toxic metals such as cadmium, and protection against oxidative stress. However, mechanistic insights into the actions of MT have not been adequately achieved. MT contains high levels of sulfur. The mutual affinity of sulfur and transition metals makes the binding of these metals to MT thermodynamically stable. Under physiologic conditions, zinc-MT is the predominant form of the metal-binding protein. The recognition of the redox regulation of zinc release from or binding to MT provides an alternate perspective on biologic function of MT. Oxidation of the thiolate cluster by a number of mild cellular oxidants causes zinc release and formation of MT-disulfide (or thionin if all metals are released from MT, but this is unlikely to occur in vivo), which have been demonstrated in vivo. Therefore, the thermodynamic stability of zinc binding makes MT an ideal zinc reservoir in vivo, and the redox regulation of zinc mobilization enables MT function in zinc homeostasis. MT-disulfide can be reduced by glutathione in the presence of selenium catalyst, restoring the capacity of the protein to bind zinc. This MT redox cycle may play a crucial role in MT biologic function. It may link to the homeostasis of essential metals, detoxification of toxic metals and protection against oxidative stress.     

Latest news about the sulfurtransferase protein family of higher plants

Sulfurtransferases/rhodaneses (Str) comprise a group of enzymes widely distributed in all phyla which catalyze in vitro the transfer of a sulfur atom from suitable sulfur donors to nucleophilic sulfur acceptors. The best characterized Str is bovine rhodanese (EC 2.8.1.1) which catalyses in vitro the transfer of a sulfane sulfur atom from thiosulfate to cyanide, leading to the formation of sulfite and thiocyanate. Plants as well as other organisms contain many proteins carrying a typical rhodanese pattern or domain forming multi-protein families (MPF). Despite the presence of Str activities in many living organisms, the physiological role of the members of this MPF has not been established unambiguously. While in mammals these proteins are involved in the elimination of toxic cyanogenic compounds, their ubiquity suggests additional physiological functions. In plants, Str are localized in the cytoplasm, mitochondria, plastids, and nucleus. Str probably also transfer reduced sulfur onto substrates as large as peptides or proteins. Several studies in different organisms demonstrate a protein–protein interaction with members of the thioredoxin MPF indicating a role of Str in maintenance of the cellular redox homeostasis. The increased expression of several members of the Str MPF in various stress conditions could be a response to oxidative stress. In summary, data indicate that Str are involved in various essential metabolic reactions.     

Persulfide sulfur is a growth factor for cells defective in sulfur metabolism

Several systems which generate persulfide sulfur promote in vitro proliferation of L1210 murine lymphoma cells. The systems include cysteine disulfides and pyridoxal, cystamine and diamine oxidase, beta-mercaptoalcohol disulfides and an alcohol dehydrogenase, and sulfide-treated proteins and a thiol. Persulfide sulfur is very unstable at pH near 7 and an essential feature of the growth-supporting systems is the ability to generate persulfide sulfur at a very low rate for long periods of time. Methyl disulfides (R--S--S--CH3) also support growth of L1210 cells and are more stable than persulfides (R--S--S--H). The requirement for these sulfur groups by L1210 cells may be related to the fact that these cells are defective in at least two enzymes of sulfur metabolism, cystathionase and 5'-methylthioadenosine phosphorylase. These findings provide the first evidence that persulfide sulfur may have a physiological role.     

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

Adult tissue homeostasis requires a tight balance between the removal of old or damaged cells and the production of new ones. Such processes are usually driven by dedicated stem cells that reside within specific tissue locations or niches.The intestinal epithelium has a remarkable regenerative capacity, which has made it a prime paradigm for the study of stem cell-driven tissue self-renewal. The discovery of the presence of stem cells in the adult midgut of the fruit fly Drosophila melanogaster has significantly impacted our understanding of the role of stem cells in intestinal homeostasis. Here we will review the current knowledge of the main mechanisms involved in the regulation of tissue homeostasis in the adult Drosophila midgut, with a focus on the role of stem cells in this process. We will also discuss processes involving acute or chronic disruption of normal intestinal homeostasis such as damage-induced regeneration and ageing.