Biochimie最新文献

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Inside front cover-EDB 封面内页-EDB

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/S0300-9084(24)00244-X

引用次数: 0

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.04.001

Alzheimer's disease (AD) and related dementias constitute an important global health challenge. Detailed understanding of the multiple molecular mechanisms underlying their pathogenesis constitutes a clue for the management of the disease. Kallikrein-related peptidases (KLKs), a lead family of serine proteases, have emerged as potential biomarkers and therapeutic targets in the context of AD and associated cognitive decline. Hence, KLKs were proposed to display multifaceted impacts influencing various aspects of neurodegeneration, including amyloid-beta aggregation, tau pathology, neuroinflammation, and synaptic dysfunction. We propose here a comprehensive survey to summarize recent findings, providing an overview of the main kallikreins implicated in AD pathophysiology namely KLK8, KLK6 and KLK7. We explore the interplay between KLKs and key AD molecular pathways, shedding light on their significance as potential biomarkers for early disease detection. We also discuss their pertinence as therapeutic targets for disease-modifying interventions to develop innovative therapeutic strategies aimed at halting or ameliorating the progression of AD and associated dementias.

阿尔茨海默病（AD）和相关痴呆症是全球健康面临的一项重要挑战。详细了解这些疾病发病的多种分子机制是治疗这些疾病的线索。Kallikrein相关肽酶（KLKs）是丝氨酸蛋白酶的一个主要家族，已成为AD和相关认知能力下降的潜在生物标志物和治疗靶点。因此，KLKs 被认为会对神经退行性病变的各个方面产生多方面的影响，包括淀粉样蛋白-β聚集、tau 病理学、神经炎症和突触功能障碍。我们在此提出一项全面调查，总结最近的研究结果，概述与 AD 病理生理学有关的主要 Kallikreins，即 KLK8、KLK6 和 KLK7。我们探讨了 KLKs 与关键的 AD 分子通路之间的相互作用，揭示了它们作为早期疾病检测的潜在生物标记物的意义。我们还讨论了它们作为疾病改变干预治疗靶点的相关性，以开发创新的治疗策略，阻止或改善注意力缺失症和相关痴呆症的进展。

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引用次数: 0

PA28γ, the ring that makes tumors invisible to the immune system? PA28γ，能让免疫系统看不见肿瘤的环？

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.04.003

PA28γ is a proteasomal interactor whose main and most known function is to stimulate the hydrolytic activity of the 20 S proteasome independently of ubiquitin and ATP. Unlike its two paralogues, PA28α and PA28β, PA28γ is largely present in the nuclear compartment and plays pivotal functions in important pathways such as cellular division, apoptosis, neoplastic transformation, chromatin structure and organization, fertility, lipid metabolism, and DNA repair mechanisms. Although it is known that a substantial fraction of PA28γ is found in the cell in a free form (i.e. not associated with 20 S), almost all of the studies so far have focused on its ability to modulate proteasomal enzymatic activities. In this respect, the ability of PA28γ to strongly stimulate degradation of proteins, especially if intrinsically disordered and therefore devoid of three-dimensional tightly folded structure, appears to be the main molecular mechanism underlying its multiple biological effects. Initial studies, conducted more than 20 years ago, came to the conclusion that among the many biological functions of PA28γ, the immunological ones were rather limited and circumscribed. In this review, we focus on recent evidence showing that PA28γ fulfills significant functions in cell-mediated acquired immunity, with a particular role in attenuating MHC class I antigen presentation, especially in relation to neoplastic transformation and autoimmune diseases.

PA28γ 是一种蛋白酶体互作因子，其最主要和最已知的功能是在泛素和 ATP 之外刺激 20 S 蛋白酶体的水解活性。与 PA28α 和 PA28β 这两个类似物不同，PA28γ 主要存在于核区，在细胞分裂、细胞凋亡、肿瘤转化、染色质结构和组织、生育、脂质代谢和 DNA 修复机制等重要途径中发挥着关键作用。尽管已知 PA28γ 有很大一部分是以游离形式（即不与 20 S 结合）存在于细胞中，但迄今为止几乎所有的研究都集中在其调节蛋白酶体酶活性的能力上。在这方面，PA28γ 强烈刺激蛋白质降解的能力似乎是其多种生物效应的主要分子机制，尤其是在蛋白质内在无序因而缺乏三维紧密折叠结构的情况下。20 多年前进行的初步研究得出的结论是，在 PA28γ 的众多生物学功能中，免疫学功能是相当有限和局限的。在这篇综述中，我们将重点讨论最近的证据，这些证据表明 PA28γ 在细胞介导的获得性免疫中发挥着重要功能，尤其是在减弱 MHC I 类抗原呈递方面，特别是在肿瘤转化和自身免疫性疾病方面。

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引用次数: 0

ProteoCure: A European network to fine-tune the proteome ProteoCure：欧洲蛋白质组微调网络。

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.06.004

Proteins are essential molecular actors in every cellular process. From their synthesis to their degradation, they are subject to continuous quality control mechanisms to ensure that they fulfil cellular needs in proper and timely fashion.

Proteostasis is a key process allowing cells or organisms to maintain an appropriate but dynamic equilibrium of their proteome (the ensemble of all their proteins). It relies on multiple mechanisms that together control the level, fate and function of individual proteins, and ensure elimination of abnormal ones. The proteostasis network is essential for development and adaptation to environmental changes or challenges. Its dysfunctions can lead to accumulation of deleterious proteins or, conversely, to excessive degradation of beneficial ones, and are implicated in many diseases such as cancers, neurodegeneration, or developmental and aging disorders. Manipulating this network to control abundance of selected target proteins is therefore a strategy with enormous therapeutic or biotechnological potential.

The ProteoCure COST Action gathers more than 350 researchers and their teams (31 countries represented) from the academic, clinical, and industrial sectors, who share the conviction that our understanding of proteostasis is mature enough to develop novel and highly specific therapies based on selective tuning of protein levels. Towards this objective, the Action organizes community-building activities to foster synergies among its participants and reinforce training of the next generation of European researchers. Its ambition is to function as a knowledge-based network and a creative exchange hub on normal and pathologic proteostasis, focusing on developing innovative tools modulating the level of specific protein(s).

蛋白质是每个细胞过程中必不可少的分子角色。从合成到降解，它们都要接受持续的质量控制机制，以确保它们能适当、及时地满足细胞的需要。蛋白质稳态是细胞或生物体维持其蛋白质组（所有蛋白质的集合体）适当但动态平衡的关键过程。它依靠多种机制共同控制单个蛋白质的水平、命运和功能，并确保消除异常蛋白质。蛋白稳态网络对于发育和适应环境变化或挑战至关重要。它的功能失调会导致有害蛋白质的积累，或者相反，导致有益蛋白质的过度降解，并与癌症、神经变性、发育和衰老障碍等许多疾病有关。因此，操纵这一网络来控制选定目标蛋白质的丰度是一种具有巨大治疗或生物技术潜力的策略。ProteoCure COST 行动汇聚了来自学术界、临床界和工业界的 350 多名研究人员及其团队（31 个国家），他们都坚信，我们对蛋白稳态的认识已经足够成熟，可以在选择性调节蛋白质水平的基础上开发出新型和高度特异性疗法。为实现这一目标，该行动组织了社区建设活动，以促进参与者之间的协同作用，并加强对下一代欧洲研究人员的培训。该行动的目标是成为一个以知识为基础的网络，以及正常和病理蛋白稳态的创造性交流中心，重点开发调节特定蛋白质水平的创新工具。

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引用次数: 0

Assessing N-terminal acetylation status of cellular proteins via an antibody specific for acetylated methionine 通过乙酰化蛋氨酸特异性抗体评估细胞蛋白质的 N 端乙酰化状态。

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.07.007

Silje Kathrine Larsen , Åse K. Bekkelund , Nina Glomnes , Thomas Arnesen , Henriette Aksnes

N-terminal acetylation is being recognized as a factor affecting protein lifetime and proteostasis. It is a modification where an acetyl group is added to the N-terminus of proteins, and this occurs in 80 % of the human proteome. N-terminal acetylation is catalyzed by enzymes called N-terminal acetyltransferases (NATs). The various NATs acetylate different N-terminal amino acids, and methionine is a known target for some of the NATs. Currently, the acetylation status of most proteins can only be assessed with a limited number of methods, including mass spectrometry, which although powerful and robust, remains laborious and can only survey a fraction of the proteome. We here present testing of an antibody that was developed to specifically recognize Nt-acetylated methionine-starting proteins. We have used dot blots with synthetic acetylated and non-acetylated peptides in addition to protein analysis of lysates from NAT knockout cell lines to assess the specificity and application of this anti-Nt-acetylated methionine antibody (anti-NtAc-Met). Our results demonstrate that this antibody is indeed NtAc-specific and further show that it has selectivity for some subtypes of methionine-starting N-termini, specifically potential substrates of the NatC, NatE and NatF enzymes. We propose that this antibody may be a powerful tool to identify NAT substrates or to analyse changes in N-terminal acetylation for specific cellular proteins of interest.

N 端乙酰化被认为是影响蛋白质寿命和蛋白稳态的一个因素。这是一种在蛋白质 N 端添加乙酰基的修饰，80% 的人类蛋白质组都存在这种情况。N 端乙酰化由称为 N 端乙酰转移酶（NATs）的酶催化。各种 NATs 对不同的 N 端氨基酸进行乙酰化，蛋氨酸是某些 NATs 的已知靶标。目前，大多数蛋白质的乙酰化状态只能通过有限的几种方法进行评估，其中包括质谱法，虽然质谱法功能强大、稳健，但仍然很费力，而且只能检测蛋白质组的一部分。我们在此介绍一种抗体的测试结果，该抗体可特异性识别 Nt-乙酰化蛋氨酸起始蛋白。除了对 NAT KO 细胞系裂解物进行蛋白质分析外，我们还使用合成乙酰化和非乙酰化肽进行点印迹，以评估这种抗 Nt-乙酰化蛋氨酸抗体（抗 NtAc-Met）的特异性和应用。我们的研究结果表明，该抗体确实具有 NtAc 特异性，并进一步表明它对某些亚型蛋氨酸起始 N-端具有选择性，特别是对 NatC、NatE 和 NatF 酶的潜在底物具有选择性。我们认为，该抗体可能是鉴定 NAT 底物或分析特定细胞蛋白 N 端乙酰化变化的有力工具。

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引用次数: 0

Cytoskeletal β-tubulin and cysteine cathepsin L deregulation by SARS-CoV-2 spike protein interaction with the neuronal model cell line SH-SY5Y SARS-CoV-2尖峰蛋白与神经元模型细胞株SH-SY5Y相互作用导致细胞骨架β-微管蛋白和半胱氨酸酪蛋白酶L失调。

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.02.006

SARS-CoV-2 mainly infects the respiratory tract but can also target other organs, including the central nervous system. While it was recently shown that cells of the blood-brain-barrier are permissive to SARS-CoV-2 infection in vitro, it remains debated whether neurons can be infected. In this study, we demonstrate that vesicular stomatitis virus particles pseudotyped with the spike protein of SARS-CoV-2 variants WT, Alpha, Delta and Omicron enter the neuronal model cell line SH-SY5Y. Cell biological analyses of the pseudo-virus treated cultures showed marked alterations in microtubules of SH-SY5Y cells. Because the changes in β-tubulin occurred in most cells, but only few were infected, we further asked whether interaction of the cells with spike protein might be sufficient to cause molecular and structural changes. For this, SH-SY5Y cells were incubated with trimeric spike proteins for time intervals of up to 24 h. CellProfiler™-based image analyses revealed changes in the intensities of microtubule staining in spike protein-incubated cells. Furthermore, expression of the spike protein-processing protease cathepsin L was found to be up-regulated by wild type, Alpha and Delta spike protein pseudotypes and cathepsin L was found to be secreted from spike protein-treated cells. We conclude that the mere interaction of the SARS-CoV-2 with neuronal cells can affect cellular architecture and proteolytic capacities. The molecular mechanisms underlying SARS-CoV-2 spike protein induced cytoskeletal changes in neuronal cells remain elusive and require future studies.

SARS-CoV-2 主要感染呼吸道，但也可能感染其他器官，包括中枢神经系统。虽然最近有研究表明，血脑屏障细胞在体外对 SARS-CoV-2 感染是允许的，但神经元是否会受到感染仍存在争议。在这项研究中，我们证明了以 SARS-CoV-2 变体 WT、Alpha、Delta 和 Omicron 的尖峰蛋白为伪型的水泡性口炎病毒颗粒能进入神经元模型细胞株 SH-SY5Y。对经过伪病毒处理的培养物进行的细胞生物学分析表明，SH-SY5Y 细胞的微管发生了明显变化。由于β-微管蛋白的变化发生在大多数细胞中，但只有少数细胞受到感染，我们进一步询问细胞与尖峰蛋白的相互作用是否足以引起分子和结构的变化。为此，我们将 SH-SY5Y 细胞与三聚尖峰蛋白孵育了 24 小时。基于 CellProfiler™ 的图像分析显示了尖峰蛋白培养细胞中微管染色强度的变化。此外，我们还发现野生型、α和δ尖峰蛋白假型上调了尖峰蛋白加工蛋白酶cathepsin L的表达，并发现尖峰蛋白处理过的细胞分泌了cathepsin L。我们的结论是，SARS-CoV-2 与神经细胞的相互作用就能影响细胞结构和蛋白水解能力。SARS-CoV-2尖峰蛋白诱导神经元细胞的细胞骨架变化的分子机制仍然难以捉摸，需要今后进行研究。

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引用次数: 0

Thrombin stories in the gut 凝血酶在肠道中的故事

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.03.007

Many studies have demonstrated the involvement of proteases in gut physiology and pathophysiology over the recent years. Among them, thrombin has appeared for a long time as an old player only involved in blood clotting upon tissue injury. The fact that thrombin receptors (Protease-Activated Receptors-1 and -4) are expressed and functional in almost all cell types of the gut, contributing to barrier, immune or motility functions, suggested that thrombin could actually be at the crossroad of intestinal physiology. Recent work has unraveled the constitutive release of active thrombin by intestinal epithelial cells, opening new research avenues on the role of thrombin in the gut. These roles are considered in the present review, as well as the regulation of thrombin in the gut. The potential of thrombin as a target for treatments of intestinal pathologies is also discussed here.

近年来，许多研究表明蛋白酶参与了肠道生理和病理生理学。其中，凝血酶长期以来一直是一个老角色，只参与组织损伤后的血液凝固。事实上，凝血酶受体（蛋白酶激活受体-1 和-4）在肠道几乎所有细胞类型中都有表达和功能，对屏障、免疫或运动功能有贡献，这表明凝血酶实际上可能处于肠道生理的十字路口。最近的研究揭示了肠上皮细胞会持续释放活性凝血酶，为凝血酶在肠道中的作用开辟了新的研究途径。本综述将探讨这些作用以及凝血酶在肠道中的调节作用。本文还讨论了凝血酶作为肠道病变治疗靶点的潜力。

引用次数: 0

Cathepsin D inhibition during neuronal differentiation selectively affects individual proteins instead of overall protein turnover 在神经元分化过程中抑制胰蛋白酶 D 会选择性地影响单个蛋白质，而不是整体蛋白质的周转。

IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-11-01 DOI: 10.1016/j.biochi.2024.03.013

Cathepsin D (CTSD) is a lysosomal aspartic protease and its inherited deficiency causes a severe pediatric neurodegenerative disease called neuronal ceroid lipofuscinosis (NCL) type 10. The lysosomal dysfunction in the affected patients leads to accumulation of undigested lysosomal cargo especially in none-dividing cells, such as neurons, resulting in death shortly after birth. To explore which proteins are mainly affected by the lysosomal dysfunction due to CTSD deficiency, Lund human mesencephalic (LUHMES) cells, capable of inducible dopaminergic neuronal differentiation, were treated with Pepstatin A. This inhibitor of “acidic” aspartic proteases caused accumulation of acidic intracellular vesicles in differentiating LUHMES cells. Pulse-chase experiments involving stable isotope labelling with amino acids in cell culture (SILAC) with subsequent mass-spectrometric protein identification and quantification were performed. By this approach, we studied the degradation and synthesis rates of 695 and 680 proteins during early and late neuronal LUHMES differentiation, respectively. Interestingly, lysosomal bulk proteolysis was not altered upon Pepstatin A treatment. Instead, the protease inhibitor selectively changed the turnover of individual proteins. Especially proteins belonging to the mitochondrial energy supply system were differentially degraded during early and late neuronal differentiation indicating a high energy demand as well as stress level in LUHMES cells treated with Pepstatin A.

溶酶体蛋白酶 D（CTSD）是一种溶酶体天冬氨酸蛋白酶，其遗传性缺乏会导致一种严重的儿科神经退行性疾病--神经细胞类脂质沉着病（NCL）10 型。受影响患者的溶酶体功能障碍会导致未消化的溶酶体货物堆积，尤其是在神经元等非分裂细胞中，从而导致患者出生后不久即死亡。为了探究CTSD缺乏症导致的溶酶体功能障碍主要影响哪些蛋白质，研究人员用Pepstatin A处理了能诱导多巴胺能神经元分化的伦德人间脑（LUHMES）细胞，这种 "酸性 "天冬氨酸蛋白酶抑制剂会导致分化中的LUHMES细胞内酸性囊泡的积累。我们进行了细胞培养中氨基酸稳定同位素标记（SILAC）的脉冲追逐实验，随后进行了质谱蛋白质鉴定和定量。通过这种方法，我们研究了神经元LUHMES分化早期和晚期分别有695和680种蛋白质的降解和合成率。有趣的是，Pepstatin A 处理并没有改变溶酶体的大量蛋白水解。相反，蛋白酶抑制剂选择性地改变了单个蛋白质的周转。特别是属于线粒体能量供应系统的蛋白质在神经元分化早期和晚期出现了不同程度的降解，这表明在使用 Pepstatin A 处理的 LUHMES 细胞中存在高能量需求和应激水平。

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IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-09-11 DOI: 10.1016/S0300-9084(24)00204-9

引用次数: 0

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IF 3.3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimie

Pub Date : 2024-08-19 DOI: 10.1016/S0300-9084(24)00183-4

引用次数: 0

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