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Modeling respiratory tract diseases for clinical translation employing conditionally reprogrammed cells 利用条件重编程细胞建立呼吸道疾病模型，促进临床转化

Cell insight

Pub Date : 2024-09-18 DOI: 10.1016/j.cellin.2024.100201

Preclinical models serve as indispensable tools in translational medicine. Specifically, patient-derived models such as patient-derived xenografts (PDX), induced pluripotent stem cells (iPSC), organoids, and recently developed technique of conditional reprogramming (CR) have been employed to reflect the host characteristics of diseases. CR technology involves co-culturing epithelial cells with irradiated Swiss-3T3-J2 mouse fibroblasts (feeder cells) in the presence of a Rho kinase (ROCK) inhibitor, Y-27632. CR technique facilitates the rapid conversion of both normal and malignant cells into a “reprogrammed stem-like” state, marked by robust in vitro proliferation. This is achieved without reliance on exogenous gene expression or viral transfection, while maintaining the genetic profile of the parental cells. So far, CR technology has been used to study biology of diseases, targeted therapies (precision medicine), regenerative medicine, and noninvasive diagnosis and surveillance. Respiratory diseases, ranking as the third leading cause of global mortality, pose a significant burden to healthcare systems worldwide. Given the substantial mortality and morbidity rates of respiratory diseases, efficient and rapid preclinical models are imperative to accurately recapitulate the diverse spectrum of respiratory conditions. In this article, we discuss the applications and future potential of CR technology in modeling various respiratory tract diseases, including lung cancer, respiratory viral infections (such as influenza and Covid-19 and etc.), asthma, cystic fibrosis, respiratory papillomatosis, and upper aerodigestive track tumors. Furthermore, we discuss the potential utility of CR in personalized medicine, regenerative medicine, and clinical translation.

临床前模型是转化医学不可或缺的工具。具体来说，患者衍生模型，如患者衍生异种移植（PDX）、诱导多能干细胞（iPSC）、器官组织以及最近开发的条件重编程（CR）技术，都被用来反映疾病的宿主特征。条件重编程技术包括在Rho激酶（ROCK）抑制剂Y-27632的作用下，将上皮细胞与经过辐照的Swiss-3T3-J2小鼠成纤维细胞（饲养细胞）进行共培养。CR技术有助于将正常细胞和恶性细胞快速转化为 "重编程干样 "状态，其特点是体外增殖强劲。实现这一目标无需依赖外源基因表达或病毒转染，同时还能保持亲代细胞的遗传特征。迄今为止，CR 技术已被用于疾病生物学研究、靶向治疗（精准医疗）、再生医学以及无创诊断和监测。呼吸系统疾病是导致全球死亡的第三大原因，给全球医疗系统造成了沉重负担。鉴于呼吸系统疾病的死亡率和发病率都很高，因此必须建立高效、快速的临床前模型，以准确再现各种呼吸系统疾病。本文将讨论 CR 技术在各种呼吸道疾病建模中的应用和未来潜力，包括肺癌、呼吸道病毒感染（如流感和 Covid-19 等）、哮喘、囊性纤维化、呼吸道乳头状瘤病和上消化道肿瘤。此外，我们还讨论了 CR 在个性化医学、再生医学和临床转化方面的潜在用途。

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引用次数: 0

The role of SUMOylation in biomolecular condensate dynamics and protein localization SUMOylation 在生物分子凝聚动态和蛋白质定位中的作用

Cell insight

Pub Date : 2024-09-10 DOI: 10.1016/j.cellin.2024.100199

As a type of protein post-translational modification, SUMOylation is the process that attaches a small ubiquitin-like modifier (SUMO) to lysine residues of protein substrates. Not only do SUMO and ubiquitin exhibit structure similarity, but the enzymatic cascades for SUMOylation and ubiquitination are also similar. It is well established that protein ubiquitination triggers proteasomal degradation, but the function of SUMOylation remains poorly understood compared to ubiquitination. Recent studies reveal the role of SUMOylation in regulating protein localization, stability, and interaction networks. SUMO can be covalently attached to substrates either as an individual monomer (monoSUMOylation) or as a polymeric SUMO chain (polySUMOylation). Strikingly, mono- and polySUMOylation likely play distinct roles in protein subcellular localization and the assembly/disassembly of biomolecular condensates, which are membraneless cellular compartments with concentrated biomolecules. In this review, we summarize the recent advances in the understanding of the function and regulation of SUMOylation, which could reveal potential therapeutic targets in disease pathogenesis.

作为蛋白质翻译后修饰的一种，SUMOylation 是一种将小型泛素样修饰物（SUMO）连接到蛋白质底物赖氨酸残基上的过程。SUMO 和泛素不仅结构相似，而且 SUMOylation 和泛素化的酶级联也很相似。蛋白质泛素化会引发蛋白酶体降解，这一点已得到公认，但与泛素化相比，人们对 SUMOylation 的功能仍然知之甚少。最近的研究揭示了 SUMOylation 在调节蛋白质定位、稳定性和相互作用网络中的作用。SUMO 可以以单个单体（单SUMOylation）或聚合 SUMO 链（聚 SUMOylation）的形式共价连接到底物上。令人震惊的是，单SUMO酰化和多SUMO酰化可能在蛋白质亚细胞定位和生物分子凝聚体的组装/解组装过程中发挥着不同的作用。在这篇综述中，我们总结了对 SUMOylation 功能和调控的最新认识进展，这些进展可能揭示了疾病发病机制中的潜在治疗靶点。

引用次数: 0

Hypoxic reactivation of Kaposi's sarcoma associated herpesvirus 卡波西肉瘤相关疱疹病毒的缺氧再活化

Cell insight

Pub Date : 2024-09-07 DOI: 10.1016/j.cellin.2024.100200

Hypoxic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) refers to the phenomenon under low oxygen where the virus goes from latent to lytic replication. Typically, healthy cells generally cease cell division and DNA replication under hypoxic conditions due to limited resources, and the presence of physiological inhibitors. This restricted replication under hypoxic conditions is considered an employed strategy of the cell to minimize energy consumption. However, cancerous cells continuously replicate and divide in hypoxic conditions by reprogramming several aspects of their cell physiology, including but not limited to metabolism, cell cycle, DNA replication, transcription, translation, and the epigenome. KSHV infection, similar to cancerous cells, is known to bypass hypoxia-induced restrictions and undergo reactivation to produce progeny viruses. In previous studies we have mapped several aspects of cell physiology that are manipulated by KSHV through its latent antigens during hypoxic conditions, which allows for a permissive environment for its replication. We discuss the major strategies utilized by KSHV to bypass hypoxia-induced repression. We also describe the KSHV-encoded antigens responsible for modulating these cellular processes important for successful viral replication and persistence in hypoxia.

卡波西肉瘤相关疱疹病毒（KSHV）的缺氧再活化是指在低氧条件下，病毒从潜伏复制到溶解复制的现象。通常情况下，健康细胞在缺氧条件下会因资源有限和存在生理抑制剂而停止细胞分裂和 DNA 复制。在缺氧条件下限制复制被认为是细胞为尽量减少能量消耗而采取的一种策略。然而，癌细胞在缺氧条件下通过重编程其细胞生理的几个方面，包括但不限于新陈代谢、细胞周期、DNA 复制、转录、翻译和表观基因组，不断进行复制和分裂。已知 KSHV 感染与癌细胞类似，会绕过缺氧诱导的限制，重新激活产生后代病毒。在之前的研究中，我们绘制了 KSHV 在缺氧条件下通过其潜伏抗原操纵细胞生理学的几个方面，从而为其复制创造了有利环境。我们讨论了 KSHV 用来绕过缺氧诱导的抑制的主要策略。我们还描述了负责调节这些细胞过程的 KSHV 编码抗原，这些细胞过程对于病毒在缺氧条件下成功复制和持续存在非常重要。

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引用次数: 0

Insights into mosquito-borne arbovirus receptors 对蚊媒虫媒病毒受体的认识

Cell insight

Pub Date : 2024-08-24 DOI: 10.1016/j.cellin.2024.100196

The increasing global prevalence of mosquito-borne viruses has emerged as a significant threat to human health and life. Identifying receptors for these viruses is crucial for improving our knowledge of viral pathogenesis and developing effective antiviral strategies. The widespread application of CRISPR-Cas9 screening have led to the discovery of many mosquito-borne virus receptors. The revealed structures of virus-receptor complexes also provide important information for understanding their interaction mechanisms. This review provides a comprehensive summary of both conventional and novel approaches for identifying new viral receptors and the putative entry factors of the most prevalent mosquito-borne viruses within the Flaviviridae, Togaviridae, and Bunyavirales. At the same time, we emphasize the common receptors utilized by these viruses for entry into both vertebrate hosts and mosquito vectors. We discuss promising avenues for developing anti-mosquito-borne viral strategies that target these receptors. Notably, targeting universal receptors of specific mosquito-borne viruses in both vertebrates and mosquitoes offers dual benefits for disease prevention. Additionally, the widespread use of AI-based machine learning and protein structure prediction will accelerate the identification of new viral receptors and provide new avenues for antiviral drug discovery.

蚊媒病毒在全球日益流行，已成为人类健康和生命的重大威胁。鉴定这些病毒的受体对于提高我们对病毒致病机理的认识和开发有效的抗病毒策略至关重要。CRISPR-Cas9 筛选技术的广泛应用发现了许多蚊媒病毒受体。所揭示的病毒-受体复合物结构也为了解其相互作用机制提供了重要信息。本综述全面总结了鉴定新病毒受体的传统方法和新方法，以及弗拉维病毒科、妥加病毒科和布尼亚病毒科中最流行的蚊媒病毒的假定进入因子。同时，我们强调了这些病毒在进入脊椎动物宿主和蚊子载体时所利用的共同受体。我们讨论了针对这些受体开发抗蚊媒病毒策略的可行途径。值得注意的是，以脊椎动物和蚊子中特定蚊媒病毒的通用受体为靶标可为疾病预防带来双重益处。此外，基于人工智能的机器学习和蛋白质结构预测的广泛应用将加速新病毒受体的鉴定，并为抗病毒药物的发现提供新的途径。

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引用次数: 0

Replication-coupled inheritance of chromatin states 染色质状态的复制耦合遗传

Cell insight

Pub Date : 2024-08-23 DOI: 10.1016/j.cellin.2024.100195

During the development of eukaryote, faithful inheritance of chromatin states is central to the maintenance of cell fate. DNA replication poses a significant challenge for chromatin state inheritance because every nucleosome in the genome is disrupted as the replication fork passes. It has been found that many factors including DNA polymerases, histone chaperones, as well as, RNA Pol II and histone modifying enzymes coordinate spatially and temporally to maintain the epigenome during this progress. In this review, we provide a summary of the detailed mechanisms of replication-coupled nucleosome assembly and post-replication chromatin maturation, highlight the inheritance of chromatin states and epigenome during these processes, and discuss the future directions and challenges in this field.

在真核生物的发育过程中，染色质状态的忠实遗传是维持细胞命运的核心。DNA 复制给染色质状态的遗传带来了巨大挑战，因为复制叉经过时，基因组中的每个核小体都会被打乱。研究发现，在这一过程中，包括 DNA 聚合酶、组蛋白伴侣以及 RNA Pol II 和组蛋白修饰酶在内的许多因素在空间和时间上相互协调，以维持表观基因组。在这篇综述中，我们总结了复制耦合核小体组装和复制后染色质成熟的详细机制，强调了这些过程中染色质状态和表观基因组的遗传，并讨论了这一领域的未来方向和挑战。

引用次数: 0

The methyltransferase SETD3 regulates mRNA alternative splicing through interacting with hnRNPK 甲基转移酶 SETD3 通过与 hnRNPK 相互作用调节 mRNA 的替代剪接

Cell insight

Pub Date : 2024-08-23 DOI: 10.1016/j.cellin.2024.100198

The methyltransferase SETD3 is an enzyme essential for catalyzing histidine-73 methylation on β-Actin, thereby promoting its polymerization and regulating muscle contraction. Although increasing evidence suggests that SETD3 is involved in multiple physiological or pathological events, its biological functions remain incompletely understood. In this study, we utilize in situ proximity labeling combined with mass spectrometry analysis to detect potential interacting partners of SETD3. Unexpectedly, we find that many splicing factors are associated with SETD3. Genome-wide RNA sequencing reveals that SETD3 regulates pre-mRNA splicing events, predominantly influencing exon skipping. Biochemical and bioinformatic analyses suggest that SETD3 interacts with hnRNPK, and they collaboratively regulate exon skipping in a common subset of genes. Functionally, we demonstrate that SETD3 and hnRNPK are required for retention of exon 7 skipping in the FNIP1 gene. This promotes FNIP1-mediated nuclear translocation of the transcription factor TFEB and the subsequent induction of lysosomal and mitochondrial biogenesis. Overall, this study uncovers a novel function of SETD3 in modulating mRNA exon splicing.

甲基转移酶 SETD3 是催化 β-肌动蛋白上组氨酸-73 甲基化，从而促进其聚合并调节肌肉收缩的重要酶。尽管越来越多的证据表明 SETD3 参与了多种生理或病理事件，但对其生物学功能的了解仍不全面。在这项研究中，我们利用原位接近标记结合质谱分析来检测 SETD3 的潜在相互作用伙伴。意外的是，我们发现许多剪接因子都与 SETD3 相关。全基因组 RNA 测序显示，SETD3 可调控前 mRNA 剪接事件，主要影响外显子跳接。生化和生物信息学分析表明，SETD3 与 hnRNPK 相互作用，它们在一个共同的基因子集中共同调控外显子跳转。在功能上，我们证明 SETD3 和 hnRNPK 是保留 FNIP1 基因第 7 外显子跳越的必要条件。这促进了 FNIP1 介导的转录因子 TFEB 的核转位，并随后诱导溶酶体和线粒体的生物生成。总之，这项研究发现了 SETD3 在调节 mRNA 外显子剪接方面的新功能。

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引用次数: 0

Mechanism of TBK1 activation in cancer cells 癌细胞中 TBK1 的激活机制

Cell insight

Pub Date : 2024-08-22 DOI: 10.1016/j.cellin.2024.100197

TANK-binding kinase 1 (TBK1) is a serine/threonine kinase with well-established roles as a central player in innate immune signaling. Dysregulation of TBK1 activity has been implicated in a variety of pathophysiologic conditions, including cancer. Generally, TBK1 acts as an oncogene and increased TBK1 activity, indicated by increased phosphorylation at the Ser172 residue, can be observed in multiple human cancers. TBK1 can be activated either by autophosphorylation of Ser172 or transphosphorylation at this site by upstream kinases. Serving as a hub for integrating numerous extracellular and intracellular signals, TBK1 can be activated through multiple signaling pathways. However, the direct upstream kinase responsible for TBK1 activation remains elusive, which limits our comprehensive understanding of its activation mechanism and potential therapeutic application targeting TBK1-related signaling especially in cancer. In this review, we summarize the findings on mechanisms of TBK1 activation in cancer cells and recent discoveries that shed light on the direct upstream kinases promoting TBK1 activation.

TANK 结合激酶 1（TBK1）是一种丝氨酸/苏氨酸激酶，在先天性免疫信号传导中发挥着重要作用。TBK1 活性失调与包括癌症在内的多种病理生理状况有关。一般来说，TBK1 是一种致癌基因，在多种人类癌症中都可观察到 TBK1 活性的增加，其表现为 Ser172 残基的磷酸化增加。TBK1 可通过 Ser172 的自身磷酸化或上游激酶在该位点的转磷酸化而激活。作为整合众多细胞外和细胞内信号的枢纽，TBK1 可通过多种信号途径被激活。然而，负责激活 TBK1 的直接上游激酶仍然难以捉摸，这限制了我们对其激活机制的全面了解以及针对 TBK1 相关信号的潜在治疗应用，尤其是在癌症中的应用。在这篇综述中，我们总结了癌细胞中 TBK1 激活机制的研究结果，以及最近发现的促进 TBK1 激活的直接上游激酶。

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Finding new roles of classic biomolecular condensates in the nucleus: Lessons from fission yeast 寻找细胞核中经典生物分子凝聚物的新作用：裂变酵母的启示

Cell insight

Pub Date : 2024-08-05 DOI: 10.1016/j.cellin.2024.100194

Decades have passed since the initial discovery of membrane-less nuclear compartments, commonly called nuclear bodies or nuclear condensates. These compartments have drawn attention to their unique characteristics and functions, especially after introducing "liquid-liquid phase separation" to this research field. While the majority of the studies on nuclear condensates have been conducted in multicellular organisms, recent genetic, biochemical, and cell biological analyses using the fission yeast Schizosaccharomyces pombe have yielded valuable insights into biomolecular condensates. This review article focuses on two 'classic' nuclear condensates and discusses how research using fission yeast has unveiled previously unknown functions of these known nuclear bodies.

自最初发现无膜核区（通常称为核体或核凝聚体）以来，几十年过去了。特别是在将 "液-液相分离 "引入这一研究领域后，这些区室的独特特征和功能引起了人们的关注。虽然有关核凝聚体的研究大多是在多细胞生物体中进行的，但最近利用裂殖酵母（Schizosaccharomyces pombe）进行的遗传、生物化学和细胞生物学分析，对生物分子凝聚体产生了宝贵的见解。这篇综述文章重点介绍了两种 "经典 "核凝聚体，并讨论了利用裂殖酵母进行的研究如何揭示了这些已知核体以前未知的功能。

引用次数: 0

Cover 封面

Cell insight

Pub Date : 2024-08-01 DOI: 10.1016/S2772-8927(24)00042-7

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Role of the CARD8 inflammasome in HIV pathogenesis CARD8 炎症体在艾滋病毒发病机制中的作用

Cell insight

Pub Date : 2024-07-19 DOI: 10.1016/j.cellin.2024.100193

Human immunodeficiency virus (HIV) continues to be a significant global health challenge despite decades of research and advances in treatment. Substantial gaps in our understanding of the mechanisms of HIV pathogenesis and the host immune responses still exist. The interaction between HIV and these immune responses is pivotal in the disease progression to acquired immunodeficiency syndrome (AIDS). Recently, the caspase recruitment domain-containing protein 8 (CARD8) inflammasome has emerged as a crucial factor in orchestrating innate immune responses to HIV infection and exerting a substantial impact on viral pathogenesis. CARD8 restricts viral replication by detecting the activity of HIV protease. Conversely, it also contributes to the depletion of CD4⁺ T cells, a key feature of disease progression towards AIDS. The purpose of this review is to summarize the role of the CARD8 inflammasome in HIV pathogenesis, delving into its mechanisms of action and potential implications for the development of therapeutic strategies.

尽管经过几十年的研究和治疗取得了进展，人类免疫缺陷病毒（HIV）仍然是全球健康面临的重大挑战。我们对艾滋病毒发病机制和宿主免疫反应的认识仍然存在巨大差距。HIV 与这些免疫反应之间的相互作用在疾病发展为获得性免疫缺陷综合征（艾滋病）的过程中起着关键作用。最近，含 Caspase 招募域的蛋白 8（CARD8）炎性体已成为协调先天免疫对 HIV 感染反应的关键因素，并对病毒的发病机制产生了重大影响。CARD8 通过检测 HIV 蛋白酶的活性来限制病毒复制。反之，它也会导致 CD4+ T 细胞的耗竭，而这正是艾滋病病情发展的一个关键特征。本综述旨在总结 CARD8 炎性体在 HIV 发病机制中的作用，深入探讨其作用机制以及对开发治疗策略的潜在影响。

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