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pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication pTα增强mRNA翻译，增强CAR - T细胞根除实体肿瘤的能力

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-12-02 DOI: 10.1016/j.cell.2025.11.005

Yuzhe Shi, Michael A. Lopez, Ivan S. Kotchetkov, Nayan Jain, Zeguo Zhao, Leena Halim, Anton Dobrin, Karlo Perica, Sophie A. Hanina, Vinagolu K. Rajasekhar, Michael G. Kharas, Michel Sadelain

Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the β-selection developmental stage, which is driven by the pre-T cell receptor and its unique pTα chain. CARs harboring the pTα 1A domain imparted greater expansion, cytokine production, and in vivo persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.

目前的嵌合抗原受体（CAR）疗法对一系列血液系统恶性肿瘤和自身免疫性疾病有效，但对实体瘤的活性有限。为了寻找增强CAR -T细胞功能持久性和效力的有效方法，我们探索了将前T细胞特征整合到典型的基于cd28的CAR中的潜力。胸腺细胞在β选择发育阶段发生增殖爆发，这是由前t细胞受体及其独特的pTα链驱动的。在多种液体和实体肿瘤模型中，携带pTα 1A结构域的car赋予T细胞更大的扩张、细胞因子的产生和体内持久性，同时降低衰竭和更大的长期肿瘤控制。结合1A结构域的CARs显示mRNA翻译主调控因子Y-Box结合蛋白1 （YBX1）的持续磷酸化，这是增强肿瘤根除所必需的。T细胞mRNA翻译的编程为调节和增强免疫治疗开辟了另一条途径。

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引用次数: 0

Membrane potential mediates the cellular response to mechanical pressure 膜电位介导细胞对机械压力的反应

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-12-02 DOI: 10.1016/j.cell.2025.11.004

Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Jose G. Abreu, Leander Ammar, Anjali R. Neliat, Janik Schüttler, Dan-Dan Su, Christophe Dupre, Nina Catherine Benites, Xili Liu, Leonid Peshkin, Mihail Barboiu, Hugo Stocker, Marc W. Kirschner, Markus Basan

Mechanical forces influence cellular decisions to grow, die, or differentiate, through largely mysterious mechanisms. Separately, changes in resting membrane potential have been observed in development, differentiation, regeneration, and cancer. We demonstrate that membrane potential is an important mediator of cellular response to mechanical pressure. We show that mechanical forces acting on the cell change cellular biomass density, which, in turn, alters membrane potential. Membrane potential then regulates cell number density in epithelia by controlling cell growth, proliferation, and cell elimination. Mechanistically, we show that changes in membrane potential control signaling through the Hippo and mitogen-activated protein kinase (MAPK) pathways and potentially other signaling pathways that originate at the cell membrane. While many molecular interactions are known to affect Hippo signaling, the upstream signal that activates the canonical Hippo pathway at the membrane has previously been elusive. Our results establish membrane potential as an important regulator of growth and tissue homeostasis.

机械力通过很大程度上神秘的机制影响细胞的生长、死亡或分化。另外，静息膜电位的变化在发育、分化、再生和癌症中也被观察到。我们证明膜电位是细胞对机械压力反应的重要介质。我们表明，作用于细胞的机械力改变了细胞的生物量密度，这反过来又改变了膜电位。然后，膜电位通过控制细胞生长、增殖和细胞消除来调节上皮细胞的数量密度。从机制上讲，我们表明通过Hippo和丝裂原活化蛋白激酶（MAPK）途径以及潜在的起源于细胞膜的其他信号通路，膜电位控制信号通路的变化。虽然已知许多分子相互作用会影响Hippo信号传导，但激活膜上典型Hippo通路的上游信号此前一直难以捉摸。我们的研究结果表明，膜电位是生长和组织稳态的重要调节因子。

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引用次数: 0

The unique architecture of umbrella toxins permits a two-tiered molecular bet-hedging strategy for interbacterial antagonism 伞状毒素的独特结构允许两层分子下注对冲策略的细菌间拮抗

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-12-02 DOI: 10.1016/j.cell.2025.10.044

Qinqin Zhao, Jiri Vlach, Young-Jun Park, Yongjun Tan, Savannah K. Bertolli, Pooja Srinivas, Pinyu Liao, Connor R. Fitzpatrick, Jeffery L. Dangl, Parastoo Azadi, Frank DiMaio, S. Brook Peterson, Dapeng Zhang, David Veesler, Joseph D. Mougous

Bacteria exist in competitive and rapidly changing environments in which the nature of future threats cannot be easily predicted. Streptomyces coelicolor produces three antibacterial umbrella particles that harbor distinct polymorphic toxin domains and an overlapping set of six diversified lectins. Here, we show that the exquisite specificity of umbrella particles derives from lectin-mediated species-specific binding to previously undescribed hypervariable surface glycoconjugates. A cryo-electron microscopy (cryo-EM) structure of one such lectin in complex with its oligosaccharide substrate defines the molecular basis for targeting through the coordinated recognition of multiple glycan features. Biochemical and genetic studies of several target species, in conjunction with lectin-swapping experiments, support a model whereby S. coelicolor umbrella toxin diversification at the levels of lectin composition and toxin polymorphism represents a unique, two-tiered bet-hedging strategy. Bioinformatic analyses support this as a means by which the unusual architecture of umbrella toxins offers Streptomyces a generalizable strategy to antagonize an unpredictable array of competitors.

细菌存在于竞争激烈和快速变化的环境中，在这种环境中，未来威胁的性质无法轻易预测。彩色链霉菌产生三种抗菌保护伞颗粒，其中含有不同的多态毒素结构域和重叠的六种不同的凝集素。在这里，我们展示了伞状颗粒的精致特异性来自凝集素介导的物种特异性结合到以前未描述的高变表面糖缀合物。一种这样的凝集素及其寡糖底物的低温电镜（cryo-EM）结构通过协调识别多个聚糖特征来定义靶向的分子基础。几种目标物种的生化和遗传研究，结合凝集素交换实验，支持一种模型，即在凝集素组成和毒素多态性水平上的S. colelicolor伞毒素多样化代表了一种独特的两层下注对冲策略。生物信息学分析支持这一观点，因为伞状毒素的不寻常结构为链霉菌提供了一种通用的策略来对抗不可预测的竞争对手。

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引用次数: 0

An archaeal transcription factor bridges prokaryotic and eukaryotic regulatory paradigms 古细菌转录因子是原核生物和真核生物调节模式的桥梁

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-12-01 DOI: 10.1016/j.cell.2025.10.036

Fernando Medina Ferrer, Dipti D. Nayak

Archaeal transcription is a hybrid of eukaryotic and prokaryotic features: an RNA polymerase II (RNAPII)-like polymerase transcribes genes organized in circular chromosomes within cells devoid of a nucleus. Consequently, archaeal genomes are depleted of transcriptional regulators found in other domains of life. Here, we outline the discovery of a cryptic, archaea-specific family of ligand-binding regulatory transcription factors (TFs), called AmzR (archaeal metabolite-sensing zipper-like regulators). We identify AmzR using an evolution-based genetic screen and show that it is a repressor of methanogenic growth on methylamines in the archaeon Methanosarcina acetivorans. AmzR binds its target promoters as an oligomer using paired basic α-helices akin to eukaryotic leucine zippers. AmzR also binds methylamines, which reduces its DNA-binding affinity and allows it to function as a one-component system commonly found in prokaryotes, while containing a eukaryotic-like DNA-binding motif. The AmzR family of TFs are widespread in archaea and broaden the scope of innovations at the prokaryote-eukaryote interface.

古细菌转录是真核生物和原核生物特征的混合体：在没有细胞核的细胞内，RNA聚合酶II （RNAPII）样聚合酶转录环状染色体中的基因。因此，古细菌基因组中缺乏在其他生命领域中发现的转录调节因子。在这里，我们概述了一个神秘的，古细菌特异性配体结合调节转录因子（tf）家族的发现，称为AmzR（古细菌代谢物感应拉链样调节剂）。我们使用基于进化的遗传筛选鉴定了AmzR，并表明它是古菌Methanosarcina activorans中甲胺产甲烷生长的抑制因子。AmzR利用类似于真核亮氨酸拉链的配对碱性α-螺旋结合其目标启动子作为寡聚物。AmzR还能与甲胺结合，这降低了其与dna结合的亲和力，并允许其作为原核生物中常见的单组分系统发挥作用，同时含有真核生物样dna结合基序。AmzR家族的tf广泛存在于古细菌中，并拓宽了原核-真核生物界面的创新范围。

引用次数: 0

Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis 先天免疫和代谢信号通过有丝分裂诱导线粒体依赖的膜裂解

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-11-28 DOI: 10.1016/j.cell.2025.11.002

Yaqiu Wang, Jianlin Lu, Alexandre F. Carisey, Sangappa B. Chadchan, Ha Won Lee, R.K. Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E. Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G. Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P. Murphy, Thirumala-Devi Kanneganti

The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.

先天免疫激活和代谢破坏的结合在许多疾病中起着关键作用，通常导致线粒体功能障碍和氧化应激驱动发病机制。然而，在这些条件下的机制调节仍然不明确。在这里，我们报告了由先天免疫信号和代谢破坏诱导的独特的溶解性细胞死亡机制，独立于caspase活性和先前描述的焦亡，PANoptosis, necroptosis， ferroptosis和oxeiptosis。相反，经历BAX/BAK1/ bid依赖的氧化应激的线粒体维持了长时间的质膜接触，导致局部氧化损伤，这一过程被我们称为有丝分裂。这一过程随后引起膜溶解和细胞死亡，称为丝裂细胞坏死。mTORC2调节细胞死亡，mTOR抑制恢复板足的细胞骨架活性，使线粒体从膜上收缩和动员，保持完整性。在体内激活该通路以mtorc2依赖的方式使肿瘤消退。总的来说，我们的研究结果确定了一种溶解性细胞死亡模式，以响应先天免疫信号和代谢破坏的协同作用。

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引用次数: 0

Stress-induced sympathetic hyperactivation drives hair follicle necrosis to trigger autoimmunity 应激诱导的交感神经过度激活驱动毛囊坏死触发自身免疫

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-11-26 DOI: 10.1016/j.cell.2025.10.042

Emily Scott-Solomon, Shlomi Brielle, Alexander O. Mann, Mark J. Khoury, Jingyu Peng, Liana Tellez, Mackenzie Harrigan, Myrto Ziogas, H. Amalia Pasolli, Monica Cassandras, Adam J. Getzler, Rebecca Freeman, Bing Zhang, Yulia Shwartz, Judith Agudo, Ruth A. Franklin, Ya-Chieh Hsu

Stress has profound effects on health, yet how it damages tissues remains poorly understood. Here, we show that acute stress triggers rapid hair loss and initiates autoimmunity. Under stress, hyperactivated sympathetic nerves release excessive norepinephrine, causing necrosis in rapidly dividing hair follicle transit-amplifying cells (HF-TACs) while sparing most hair follicle stem cells (HFSCs). This differential sensitivity stems from differences in cell death pathways, metabolic strategies, and calcium homeostasis, which render HF-TACs more susceptible to norepinephrine-induced calcium surges. HF-TAC necrosis releases cellular debris that triggers macrophage-mediated clearance and dendritic cell activation, ultimately leading to the activation and amplification of autoreactive T cells that can attack the hair follicle under inflammatory insults. Our findings reveal mechanistically how stress causes immediate tissue damage in highly proliferative HF-TACs via sympathetic nerve-induced necrosis, which in turn fuels the activation of autoreactive T cells capable of mounting future attacks against the same tissue.

压力对健康有着深远的影响，但人们对它是如何损害组织的却知之甚少。在这里，我们表明急性应激触发快速脱发和启动自身免疫。在压力下，过度激活的交感神经释放过量的去甲肾上腺素，导致快速分裂的毛囊转运扩增细胞（HF-TACs）坏死，同时保留大多数毛囊干细胞（HFSCs）。这种不同的敏感性源于细胞死亡途径、代谢策略和钙稳态的差异，这使得hf - tac更容易受到去甲肾上腺素诱导的钙激增的影响。HF-TAC坏死释放细胞碎片，触发巨噬细胞介导的清除和树突状细胞激活，最终导致自身反应性T细胞的激活和扩增，从而在炎症损伤下攻击毛囊。我们的研究结果揭示了压力如何通过交感神经诱导的坏死在高增殖的hf - tac中引起立即的组织损伤，这反过来又刺激了自身反应性T细胞的激活，这些T细胞能够在未来对同一组织发动攻击。

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引用次数: 0

Thermodynamic principles link in vitro transcription factor affinities to single-molecule chromatin states in cells 热力学原理将体外转录因子的亲和力与细胞中的单分子染色质状态联系起来

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-11-26 DOI: 10.1016/j.cell.2025.11.008

Julia M. Schaepe, Torbjörn Fries, Benjamin R. Doughty, Vivekanandan Ramalingam, Betty B. Liu, Olivia J. Crocker, Georgi K. Marinov, Michaela M. Hinks, Emil Marklund, William J. Greenleaf

The molecular details governing transcription factor (TF) binding and the formation of accessible chromatin are not yet quantitatively understood—including how sequence context modulates affinity, how TFs search DNA, the kinetics of TF occupancy, and how motif grammars coordinate binding. To resolve these questions for a human TF, erythroid Krüppel-like factor (eKLF/KLF1), we quantitatively compare, in high throughput, in vitro TF binding rates and affinities with in vivo single-molecule TF and nucleosome occupancies and in vivo-derived deep learning models. We find that 40-fold flanking sequence effects on affinity are consistent with distal flanks tuning TF search parameters and captured by a linear energy model. Motif recognition probability, rather than time in the bound state, drives affinity changes, and in vitro and in nuclei measurements exhibit consistent, minutes-long TF residence times. Finally, in vitro biophysical parameters predict in vivo sequence preferences and single-molecule chromatin states for unseen motif grammars.

调控转录因子（TF）结合和可接近染色质形成的分子细节尚未定量了解，包括序列上下文如何调节亲和力，TF如何搜索DNA， TF占用动力学以及基序语法如何协调结合。为了解决这些问题，我们在高通量下，定量比较了体外TF结合率和亲和力与体内单分子TF和核小体占用率以及体内衍生的深度学习模型。我们发现40倍侧翼序列对亲和力的影响与远端侧翼调谐TF搜索参数一致，并被线性能量模型捕获。基序识别概率，而不是在结合状态下的时间，驱动亲和力变化，并且在体外和细胞核测量显示一致的，几分钟长的TF停留时间。最后，体外生物物理参数预测了体内序列偏好和单分子染色质状态的未知基序语法。

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引用次数: 0

A systematic approach to tuberculosis vaccine development 开发结核病疫苗的系统方法

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-11-26 DOI: 10.1016/j.cell.2025.10.024

Chetan Seshadri

M. tuberculosis is once again the leading infectious cause of death worldwide despite the existence of a licensed vaccine (BCG). In this issue of Cell, Vidal et al. systematically evaluate 42 candidate antigens and develop a trivalent mRNA vaccine that demonstrates effective and durable protection from tuberculosis in several mouse models. This vaccine also enhances protection conferred by BCG.

尽管有一种获得许可的疫苗（卡介苗）存在，但结核分枝杆菌再次成为世界范围内导致死亡的主要传染性原因。在这一期的Cell中，Vidal等人系统地评估了42种候选抗原，并开发了一种三价mRNA疫苗，该疫苗在几种小鼠模型中显示出有效和持久的结核病保护作用。这种疫苗还能增强卡介苗的保护作用。

引用次数: 0

Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance. 癌细胞利用器官间的神经免疫回路来逃避免疫监视。

IF 42.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-11-26 Epub Date: 2025-10-24 DOI: 10.1016/j.cell.2025.09.029

Yu Zhang, Yibo Guo, Zheqi Liu, Yiting Sun, Xi Yang, Mingtao Chen, Guanying Feng, Chengzhong Lin, Yang Wang, Zhen Zhang, Yun Zhu, Jinhai Ye, Jiajia Liu, Jun Shi, Xiaomeng Zhou, Qingjian Han, Yu Liu, Qian Jiang, Youcheng Yu, Xu Wang, Chenping Zhang, Yunfan Sun, Jian Zhou, Jia Fan, Tong Ji

Whether and how cancer exploits distant organs to escape immune surveillance remains largely unknown. Using clinical data from head and neck squamous cell carcinoma (HNSCC) patients and three murine oral cancer models, we find that cancer cells under immune pressure secrete slit guidance ligand 2 (SLIT2) through an activating transcription factor 4 (ATF4)-dependent pathway, which activates tumor-innervating nociceptive neurons and aggravates cancer-induced pain. This activation then stimulates tumor-draining lymph-node (TDLN)-innervating nociceptive neurons and increases calcitonin gene-related peptide (CGRP) secretion, remodeling TDLNs into an immune-suppressed state. Consequently, decreased CCL5 secretion from immune-suppressed TDLNs promotes M2-like polarization of tumor-associated macrophages, facilitating tumor growth and reducing immune checkpoint blockade (ICB) efficacy. Targeting nociceptive neurons or the ATF4-SLIT2-CGRP axis restores immune activity, alleviates cancer-induced pain, and improves ICB responses. Our findings reveal an inter-organ neuroimmune circuit co-opted by cancer to escape immune surveillance, suggesting potential therapeutic strategies to enhance immunotherapy.

癌症是否以及如何利用远端器官来逃避免疫监视在很大程度上仍然未知。利用头颈部鳞状细胞癌（HNSCC）患者和3种小鼠口腔癌模型的临床数据，我们发现在免疫压力下的癌细胞通过激活转录因子4 （ATF4）依赖通路分泌裂隙引导配体2 (slit guidance ligand 2, SLIT2)，激活肿瘤神经支配的伤害性神经元，加重癌症引起的疼痛。这种激活随后刺激肿瘤引流淋巴结（TDLN）支配的伤害性神经元，增加降钙素基因相关肽（CGRP）的分泌，重塑TDLN进入免疫抑制状态。因此，免疫抑制的tdln分泌的CCL5减少，促进肿瘤相关巨噬细胞的m2样极化，促进肿瘤生长，降低免疫检查点阻断（ICB）的功效。靶向伤害性神经元或ATF4-SLIT2-CGRP轴可恢复免疫活性，减轻癌症引起的疼痛，并改善ICB反应。我们的研究结果揭示了一个器官间神经免疫回路被癌症吸收以逃避免疫监视，这提示了加强免疫治疗的潜在治疗策略。

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引用次数: 0

Activation-induced cytidine deaminase: The missing piece of many puzzles 激活诱导胞苷脱氨酶：许多谜题的缺失部分

IF 64.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell

Pub Date : 2025-11-26 DOI: 10.1016/j.cell.2025.10.031

Thiago Carvalho, Sidonia Fagarasan, Masamichi Muramatsu

Twenty-five years ago, two Cell papers reported the key missing functional piece in three molecular puzzles. The genetic swapping of immunoglobulin constant regions, the mutational fine-tuning of antibody specificity, and a baffling human immunodeficiency were traced to the action of one enzyme: activation-induced cytidine deaminase (AID).

25年前，《细胞》杂志的两篇论文报道了三个分子谜题中缺失的关键功能部分。免疫球蛋白恒定区域的基因交换、抗体特异性的突变微调和令人困惑的人类免疫缺陷可追溯到一种酶的作用：激活诱导胞苷脱氨酶（AID）。

引用次数: 0

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