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The high-affinity tryptophan uptake transport system in human cells. 人体细胞中的高亲和性色氨酸吸收转运系统。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230742
Keisuke Wakasugi, Takumi Yokosawa

The L-tryptophan (Trp) transport system is highly selective for Trp with affinity in the nanomolar range. This transport system is augmented in human interferon (IFN)-γ-treated and indoleamine 2,3-dioxygenase 1 (IDO1)-expressing cells. Up-regulated cellular uptake of Trp causes a reduction in extracellular Trp and initiates immune suppression. Recent studies demonstrate that both IDO1 and tryptophanyl-tRNA synthetase (TrpRS), whose expression levels are up-regulated by IFN-γ, play a pivotal role in high-affinity Trp uptake into human cells. Furthermore, overexpression of tryptophan 2,3-dioxygenase (TDO2) elicits a similar effect as IDO1 on TrpRS-mediated high-affinity Trp uptake. In this review, we summarize recent findings regarding this Trp uptake system and put forward a possible molecular mechanism based on Trp deficiency induced by IDO1 or TDO2 and tryptophanyl-AMP production by TrpRS.

L-色氨酸(Trp)转运系统对 Trp 具有高度选择性,亲和力在纳摩尔范围内。在经干扰素(IFN)-γ 处理和表达吲哚胺-2,3-二氧化酶 1(IDO1)的细胞中,这种转运系统会增强。细胞对 Trp 吸收的上调会导致细胞外 Trp 的减少,并引发免疫抑制。最近的研究表明,IDO1 和色氨酸-tRNA 合成酶(TrpRS)的表达水平受 IFN-γ 上调,它们在人类细胞吸收高亲和性 Trp 的过程中起着关键作用。此外,色氨酸 2,3-二氧合酶(TDO2)的过表达对 TrpRS 介导的高亲和性 Trp 摄取也有类似于 IDO1 的作用。在这篇综述中,我们总结了有关这一 Trp 摄取系统的最新发现,并提出了一种可能的分子机制,该机制基于 IDO1 或 TDO2 诱导的 Trp 缺乏以及 TrpRS 产生的色氨酸-AMP。
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引用次数: 0
Lessons from natural molecular glue degraders. 天然分子胶降解剂的启示
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230836
Shiyun Cao

Molecular glue (MG) degraders include plant hormones and therapeutic drugs and have become a hot topic in drug discovery. Unlike bivalent proteolysis targeting chimeras (PROTACs), monovalent MGs can trigger the degradation of non-ligandable proteins by enhancing their interaction with E3 ubiquitin ligases. Here, I analyze the characteristics of natural MG degraders, contrast them with synthetic ones, and provide a rationale for optimizing MGs. In natural MG-based degradation systems, a stable complex is only formed when all three partners (MG, E3 ligase, and substrate) are present, while the affinities between any two components are either weak or undetectable. After the substrate is degraded, the MG will dissociate from its receptor (E3 ligase) due to their low micromolar affinity. In contrast, synthetic MGs, such as immunomodulatory drugs (IMiDs) and CR8, are potent inhibitors of their receptors by blocking the CRBN-native substrate interaction or by occupying the active site of CDK12. Inspired by nature, the affinities of IMiDs to CRBN can be reduced to make those compounds degraders without the E3-inhibitory activity, therefore, minimizing the interference with the physiological substrates of CRBN. Similarly, the CR8-CDK interaction can be weakened to uncouple the degrader function from the kinase inhibition. To mimic natural examples and reduce side effects, future development of MG degraders that lack the inhibitory activity should be considered.

分子胶(MG)降解剂包括植物激素和治疗药物,已成为药物发现领域的热门话题。与二价蛋白水解靶向嵌合体(PROTACs)不同,单价MGs可以通过增强非配体蛋白与E3泛素连接酶的相互作用来触发非配体蛋白的降解。在这里,我分析了天然MG降解剂的特点,将它们与合成的MG降解剂进行了对比,并为优化MGs提供了理论依据。在基于天然 MG 的降解系统中,只有当所有三个伙伴(MG、E3 连接酶和底物)都存在时,才能形成稳定的复合物,而任何两个成分之间的亲和力要么很弱,要么无法检测到。底物降解后,由于 MG 与其受体(E3 连接酶)之间的亲和力很低,因此 MG 会与其受体解离。相反,人工合成的 MG,如免疫调节药物(IMiDs)和 CR8,通过阻断 CRBN 与原生底物的相互作用或占据 CDK12 的活性位点,成为其受体的强效抑制剂。受自然界的启发,IMiDs 与 CRBN 的亲和力可以降低,使这些化合物成为没有 E3 抑制活性的降解剂,从而最大限度地减少对 CRBN 生理底物的干扰。同样,也可以削弱 CR8 与 CDK 的相互作用,使降解剂功能与激酶抑制作用脱钩。为了模仿自然实例并减少副作用,未来应考虑开发缺乏抑制活性的 MG 降解剂。
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引用次数: 0
Proofreading mechanisms of the innate immune receptor RIG-I: distinguishing self and viral RNA. 先天性免疫受体 RIG-I 的校对机制:区分自身和病毒 RNA。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230724
Mihai Solotchi, Smita S Patel

The RIG-I-like receptors (RLRs), comprising retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), are pattern recognition receptors belonging to the DExD/H-box RNA helicase family of proteins. RLRs detect viral RNAs in the cytoplasm and respond by initiating a robust antiviral response that up-regulates interferon and cytokine production. RIG-I and MDA5 complement each other by recognizing different RNA features, and LGP2 regulates their activation. RIG-I's multilayered RNA recognition and proofreading mechanisms ensure accurate viral RNA detection while averting harmful responses to host RNAs. RIG-I's C-terminal domain targets 5'-triphosphate double-stranded RNA (dsRNA) blunt ends, while an intrinsic gating mechanism prevents the helicase domains from non-specifically engaging with host RNAs. The ATPase and RNA translocation activity of RIG-I adds another layer of selectivity by minimizing the lifetime of RIG-I on non-specific RNAs, preventing off-target activation. The versatility of RIG-I's ATPase function also amplifies downstream signaling by enhancing the signaling domain (CARDs) exposure on 5'-triphosphate dsRNA and promoting oligomerization. In this review, we offer an in-depth understanding of the mechanisms RIG-I uses to facilitate viral RNA sensing and regulate downstream activation of the immune system.

RIG-I 样受体(RLRs)包括视黄酸诱导基因 I(RIG-I)、黑色素瘤分化相关基因 5(MDA5)和遗传与生理学实验室 2(LGP2),是属于 DExD/H-box RNA 螺旋酶家族的模式识别受体。RLRs 可检测到细胞质中的病毒 RNA,并通过启动强有力的抗病毒反应,上调干扰素和细胞因子的产生。RIG-I 和 MDA5 通过识别不同的 RNA 特征来相互补充,而 LGP2 则调节它们的激活。RIG-I 的多层 RNA 识别和校对机制可确保准确检测病毒 RNA,同时避免对宿主 RNA 产生有害反应。RIG-I 的 C 端结构域靶向 5'-triphosphate 双链 RNA (dsRNA) 的钝末端,而内在的门控机制可防止螺旋酶结构域与宿主 RNA 发生非特异性结合。RIG-I 的 ATPase 和 RNA 转位活性可最大限度地减少 RIG-I 在非特异性 RNA 上的停留时间,防止脱靶激活,从而增加了另一层选择性。RIG-I 的 ATPase 功能还能增强信号结构域(CARDs)在 5'-triphosphate dsRNA 上的暴露,促进寡聚化,从而扩大下游信号传导。在这篇综述中,我们将深入了解 RIG-I 用来促进病毒 RNA 感知和调节下游免疫系统激活的机制。
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引用次数: 0
Research progress of ZIC5 for tumor metastasis. ZIC5治疗肿瘤转移的研究进展。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231263
Yiming Zhong, Shangzhi Yang, Xianli Wang, Chuanyu Sun

The zinc finger protein of the cerebellum (ZIC) family comprises five members (ZIC1-5), homologous with the odd-paired (OPA) gene in Drosophila melanogila. These transcription factors contain five Cys2His zinc finger domains, constituting one of the most abundant transcription factor families in human cells. ZIC proteins significantly contribute to transcriptional regulation and chromatin remodeling. As a member of the ZIC family, ZIC5 is essential for animal growth and development. Numerous studies have investigated the connection between ZIC proteins and cancer as well as tumor metastases in recent years. Many studies have found that within tumor tissues, the transcription and translation processes increase the expression of ZIC5 which is linked to tumor aggressiveness. This review aims to provide an objective summary of the impact of ZIC5 on tumor metastasis and consider the potential application of ZIC5 targets in both tumor therapy and the early detection of cancer.

小脑锌指蛋白(ZIC)家族由五个成员(ZIC1-5)组成,与黑腹果蝇的奇数配对(OPA)基因同源。这些转录因子含有五个 Cys2His 锌指结构域,是人类细胞中最丰富的转录因子家族之一。ZIC 蛋白对转录调控和染色质重塑有重要贡献。作为 ZIC 家族的一员,ZIC5 对动物的生长和发育至关重要。近年来,许多研究都在探讨 ZIC 蛋白与癌症以及肿瘤转移之间的联系。许多研究发现,在肿瘤组织中,转录和翻译过程会增加 ZIC5 的表达,而这与肿瘤的侵袭性有关。本综述旨在客观总结 ZIC5 对肿瘤转移的影响,并探讨 ZIC5 靶点在肿瘤治疗和癌症早期检测中的潜在应用。
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引用次数: 0
Nano-organization of synaptic calcium signaling. 突触钙信号的纳米组织
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231385
Clara I McCarthy, Ege T Kavalali

Recent studies suggest an exquisite structural nano-organization within single synapses, where sites of evoked fusion - marked by clustering of synaptic vesicles, active zone proteins and voltage-gated calcium channels - are directly juxtaposed to postsynaptic receptor clusters within nanocolumns. This direct nanometer scale alignment between presynaptic fusion apparatus and postsynaptic receptors is thought to ensure the fidelity of synaptic signaling and possibly allow multiple distinct signals to occur without interference from each other within a single active zone. The functional specificity of this organization is made possible by the inherent nano-organization of calcium signals, where all the different calcium sources such as voltage-gated calcium channels, intracellular stores and store-operated calcium entry have dedicated local targets within their nanodomain to ensure precision of action. Here, we discuss synaptic nano-organization from the perspective of calcium signals, where some of the principal findings from early work in the 1980s continue to inspire current studies that exploit new genetic tools and super-resolution imaging technologies.

最近的研究表明,在单个突触内存在一种精致的纳米结构组织,其中诱发融合的部位(以突触小泡、活性区蛋白和电压门控钙通道的聚集为标志)与纳米柱内的突触后受体群直接并列。突触前融合器和突触后受体之间这种直接的纳米级排列被认为是为了确保突触信号的保真度,并有可能使多个不同的信号在单个活跃区内不受干扰地发生。这种组织的功能特异性得益于钙信号固有的纳米组织,其中所有不同的钙源(如电压门控钙通道、细胞内贮存和贮存操作钙离子进入)在其纳米域内都有专门的局部目标,以确保作用的精确性。在这里,我们从钙信号的角度讨论突触纳米组织,20 世纪 80 年代早期工作中的一些主要发现继续启发着当前的研究,这些研究利用了新的遗传工具和超分辨率成像技术。
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引用次数: 0
Exploring the role non-coding RNAs during myocardial cell fate. 探索非编码 RNA 在心肌细胞命运中的作用
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231216
Diego Franco, Cristina Sánchez-Fernández, Carlos García-Padilla, Estefania Lozano-Velasco

Myocardial cell fate specification takes place during the early stages of heart development as the precardiac mesoderm is configured into two symmetrical sets of bilateral precursor cells. Molecular cues of the surrounding tissues specify and subsequently determine the early cardiomyocytes, that finally matured as the heart is completed at early postnatal stages. Over the last decade, we have greatly enhanced our understanding of the transcriptional regulation of cardiac development and thus of myocardial cell fate. The recent discovery of a novel layer of gene regulation by non-coding RNAs has flourished their implication in epigenetic, transcriptional and post-transcriptional regulation of cardiac development. In this review, we revised the current state-of-the-art knowledge on the functional role of non-coding RNAs during myocardial cell fate.

心肌细胞命运的指定发生在心脏发育的早期阶段,因为心肌前中胚层被配置成两组对称的双侧前体细胞。周围组织的分子线索指定并随后决定了早期心肌细胞,这些细胞最终在出生后早期心脏发育完成时成熟。在过去的十年中,我们对心脏发育的转录调控以及心肌细胞命运的了解有了很大的提高。最近,我们发现了非编码 RNA 对基因调控的一个新的层次,这使得非编码 RNA 在心脏发育的表观遗传、转录和转录后调控中的作用更加突出。在这篇综述中,我们回顾了目前关于非编码 RNA 在心肌细胞命运过程中的功能作用的最新知识。
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引用次数: 0
Mechanoimmunology in the solid tumor microenvironment. 实体肿瘤微环境中的机制免疫学。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231427
Matteo Golo, Peter L H Newman, Daryan Kempe, Maté Biro

The tumor microenvironment (TME) is a complex and dynamic ecosystem that adjoins the cancer cells within solid tumors and comprises distinct components such as extracellular matrix, stromal and immune cells, blood vessels, and an abundance of signaling molecules. In recent years, the mechanical properties of the TME have emerged as critical determinants of tumor progression and therapeutic response. Aberrant mechanical cues, including altered tissue architecture and stiffness, contribute to tumor progression, metastasis, and resistance to treatment. Moreover, burgeoning immunotherapies hold great promise for harnessing the immune system to target and eliminate solid malignancies; however, their success is hindered by the hostile mechanical landscape of the TME, which can impede immune cell infiltration, function, and persistence. Consequently, understanding TME mechanoimmunology - the interplay between mechanical forces and immune cell behavior - is essential for developing effective solid cancer therapies. Here, we review the role of TME mechanics in tumor immunology, focusing on recent therapeutic interventions aimed at modulating the mechanical properties of the TME to potentiate T cell immunotherapies, and innovative assays tailored to evaluate their clinical efficacy.

肿瘤微环境(TME)是一个复杂而动态的生态系统,它与实体瘤内的癌细胞相邻,由细胞外基质、基质和免疫细胞、血管以及大量信号分子等不同成分组成。近年来,TME 的机械特性已成为肿瘤进展和治疗反应的关键决定因素。异常的机械线索,包括组织结构和硬度的改变,会导致肿瘤的进展、转移和抗药性。此外,蓬勃发展的免疫疗法为利用免疫系统靶向消除实体恶性肿瘤带来了巨大希望;然而,它们的成功却受阻于 TME 充满敌意的机械结构,这可能会阻碍免疫细胞的浸润、功能和持久性。因此,了解TME机械免疫学--机械力与免疫细胞行为之间的相互作用--对于开发有效的实体肿瘤疗法至关重要。在此,我们回顾了TME力学在肿瘤免疫学中的作用,重点介绍了近期旨在调节TME力学特性以增强T细胞免疫疗法的治疗干预措施,以及为评估其临床疗效而量身定制的创新检测方法。
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引用次数: 0
PROPPINs and membrane fission in the endo-lysosomal system. 内溶酶体系统中的 PROPPINs 和膜裂变。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230897
Navin Gopaldass, Andreas Mayer

PROPPINs constitute a conserved protein family with multiple members being expressed in many eukaryotes. PROPPINs have mainly been investigated for their role in autophagy, where they co-operate with several core factors for autophagosome formation. Recently, novel functions of these proteins on endo-lysosomal compartments have emerged. PROPPINs support the division of these organelles and the formation of tubulo-vesicular cargo carriers that mediate protein exit from them, such as those generated by the Retromer coat. In both cases, PROPPINs provide membrane fission activity. Integrating information from yeast and human cells this review summarizes the most important molecular features that allow these proteins to facilitate membrane fission and thus provide a critical element to endo-lysosomal protein traffic.

PROPPINs 是一个保守的蛋白质家族,其多个成员在许多真核生物中都有表达。人们主要研究了 PROPPINs 在自噬过程中的作用,它们与自噬体形成过程中的几个核心因子合作。最近,人们发现了这些蛋白在内含溶酶体区室中的新功能。PROPPINs 支持这些细胞器的分裂,并支持形成管泡货物载体,从而介导蛋白质从这些细胞器中排出,例如由 Retromer 衣壳产生的载体。在这两种情况下,PROPPINs 都具有膜分裂活性。本综述综合了酵母和人类细胞的信息,总结了这些蛋白质促进膜裂解的最重要的分子特征,从而为内溶酶体蛋白质的运输提供了一个关键因素。
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引用次数: 0
Let's get fat: emergence of S-acylation as a therapeutic target in Huntington disease. 让我们胖起来:S-酰化成为亨廷顿病的治疗靶点。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231290
Dale D O Martin, Shaun S Sanders

Protein mislocalization is a key initial step in neurodegeneration, regardless of etiology, and has been linked to changes in the dynamic addition of saturated fatty acids to proteins, a process known as S-acylation. With the advent of new techniques to study S-acylation and the recent discovery of new enzymes that facilitate protein deacylation, novel small molecules are emerging as potential new therapeutic treatments. Huntington disease (HD) is a devastating, fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric deficits caused by a CAG repeat expansion in the HTT gene. The protein that is mutated in HD, huntingtin, is less S-acylated which is associated with mutant HTT aggregation and cytotoxicity. Recent exciting findings indicate that restoring S-acylation in HD models using small molecule inhibitors of the deacylation enzymes is protective. Herein, we set out to describe the known roles of S-acylation in HD and how it can be targeted for therapeutic design.

无论病因如何,蛋白质错位都是神经变性的关键第一步,它与蛋白质中饱和脂肪酸的动态添加变化有关,这一过程被称为 S-酰化。随着研究 S-酰化的新技术的出现,以及最近发现促进蛋白质脱酰化的新酶,新型小分子药物正在成为潜在的新疗法。亨廷顿病(Huntington disease,HD)是一种毁灭性的致命神经退行性疾病,其特征是由 HTT 基因中的 CAG 重复扩增引起的运动、认知和精神障碍。在 HD 中发生突变的亨廷蛋白的 S-酰化程度较低,这与突变 HTT 的聚集和细胞毒性有关。最近令人兴奋的研究结果表明,使用脱乙酰化酶的小分子抑制剂恢复 HD 模型中的 S-乙酰化具有保护作用。在此,我们将介绍S-酰化在HD中的已知作用,以及如何将其作为治疗设计的靶点。
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引用次数: 0
Mature beyond their years: young children who escape detection of parasitemia despite living in settings of intense malaria transmission. 超乎年龄的成熟:尽管生活在疟疾高度传播的环境中,但仍有幼儿未能被检测出寄生虫血症。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230401
Prasida Holla, Jyoti Bhardwaj, Tuan M Tran

Despite having the highest risk of progressing to severe disease due to lack of acquired immunity, the youngest children living in areas of highly intense malaria transmission have long been observed to be infected at lower rates than older children. Whether this observation is due to reduced exposure to infectious mosquito bites from behavioral and biological factors, maternally transferred immunity, genetic factors, or enhanced innate immunity in the young child has intrigued malaria researchers for over half a century. Recent evidence suggests that maternally transferred immunity may be limited to early infancy and that the young child's own immune system may contribute to control of malarial symptoms early in life and prior to the development of more effective adaptive immunity. Prospective studies of active and passive detection of Plasmodium falciparum blood-stage infections have identified young children (<5 years old) who remain uninfected through a defined surveillance period despite living in settings of highly intense malaria transmission. Yet, little is known about the potential immunological basis for this 'aparasitemic' phenotype. In this review, we summarize the observational evidence for this phenotype in field studies and examine potential reasons why these children escape detection of parasitemia, covering factors that are either extrinsic or intrinsic to their developing immune system. We discuss the challenges of distinguishing malaria protection from lack of malaria exposure in field studies. We also identify gaps in our knowledge regarding cellular immunity in the youngest age group and propose directions that researchers may take to address these gaps.

尽管由于缺乏获得性免疫而发展成严重疾病的风险最高,但长期以来,人们一直观察到,生活在疟疾传播高度密集地区的最年幼儿童的感染率低于年龄较大的儿童。这一观察结果究竟是由于行为和生物因素、母体转移的免疫力、遗传因素,还是幼儿先天免疫力的增强导致接触传染性蚊虫叮咬的机会减少,半个多世纪以来一直困扰着疟疾研究人员。最近的证据表明,母体转移的免疫力可能仅限于婴儿早期,而幼儿自身的免疫系统可能有助于在生命早期和更有效的适应性免疫力发展之前控制疟疾症状。对恶性疟原虫血期感染进行主动和被动检测的前瞻性研究发现,幼儿 (
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引用次数: 0
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