首页 > 最新文献

Cell Chemical Biology最新文献

英文 中文
Insights into bacterial metabolism from small RNAs 从小规模 RNA 了解细菌的新陈代谢
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.07.002
Kai Papenfort , Gisela Storz

The study of small, regulatory RNAs (sRNA) that act by base-pairing with target RNAs in bacteria has been steadily advancing, particularly with the availability of more and more transcriptome and RNA-RNA interactome datasets. While the characterization of multiple sRNAs has helped to elucidate their mechanisms of action, these studies also are providing insights into protein function, control of metabolic flux, and connections between metabolic pathways as we will discuss here. In describing several examples of the metabolic insights gained, we will summarize the different types of base-pairing sRNAs including mRNA-derived sRNAs, sponge RNAs, RNA mimics, and dual-function RNAs as well as suggest how information about sRNAs could be exploited in the future.

通过与细菌中的目标 RNA 进行碱基配对而发挥作用的小型调控 RNA(sRNA)的研究一直在稳步发展,特别是随着越来越多的转录组和 RNA-RNA 交互组数据集的出现。多种 sRNAs 的特征描述有助于阐明它们的作用机制,同时这些研究也为蛋白质功能、代谢通量控制以及代谢途径之间的联系提供了见解,我们将在这里讨论这些见解。在描述所获得的代谢洞察力的几个例子时,我们将总结不同类型的碱基配对 sRNA,包括 mRNA 衍生的 sRNA、海绵 RNA、RNA 模拟物和双重功能 RNA,并就未来如何利用 sRNA 信息提出建议。
{"title":"Insights into bacterial metabolism from small RNAs","authors":"Kai Papenfort ,&nbsp;Gisela Storz","doi":"10.1016/j.chembiol.2024.07.002","DOIUrl":"10.1016/j.chembiol.2024.07.002","url":null,"abstract":"<div><p>The study of small, regulatory RNAs (sRNA) that act by base-pairing with target RNAs in bacteria has been steadily advancing, particularly with the availability of more and more transcriptome and RNA-RNA interactome datasets. While the characterization of multiple sRNAs has helped to elucidate their mechanisms of action, these studies also are providing insights into protein function, control of metabolic flux, and connections between metabolic pathways as we will discuss here. In describing several examples of the metabolic insights gained, we will summarize the different types of base-pairing sRNAs including mRNA-derived sRNAs, sponge RNAs, RNA mimics, and dual-function RNAs as well as suggest how information about sRNAs could be exploited in the future.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1571-1577"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Meet the authors: Lydia P. Tsamouri and Daniel A. Bachovchin 与作者见面:莉迪亚-P-查穆里和丹尼尔-A-巴乔夫钦
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.012
Lydia P. Tsamouri, Daniel A. Bachovchin

In an interview with Dr. Mishtu Dey, editor-in-chief of Cell Chemical Biology, the authors of the article entitled “The hydrophobicity of the CARD8 N-terminus tunes inflammasome activation” share their perspectives on the ways chemical biology enriches immunology research, the challenges and opportunities in the field, and their scientific career paths.

在与《细胞化学生物学》主编 Mishtu Dey 博士的访谈中,题为《CARD8 N-terminus 的疏水性调节炎症小体的激活》一文的作者分享了他们对化学生物学如何丰富免疫学研究、该领域的挑战和机遇以及他们的科研道路的看法。
{"title":"Meet the authors: Lydia P. Tsamouri and Daniel A. Bachovchin","authors":"Lydia P. Tsamouri,&nbsp;Daniel A. Bachovchin","doi":"10.1016/j.chembiol.2024.08.012","DOIUrl":"10.1016/j.chembiol.2024.08.012","url":null,"abstract":"<div><p>In an interview with Dr. Mishtu Dey, editor-in-chief of <em>Cell Chemical Biology</em>, the authors of the article entitled “The hydrophobicity of the CARD8 N-terminus tunes inflammasome activation” share their perspectives on the ways chemical biology enriches immunology research, the challenges and opportunities in the field, and their scientific career paths.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1568-1570"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003611/pdfft?md5=399618023e792f8827f726e2f978ec23&pid=1-s2.0-S2451945624003611-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Membrane remodeling via ubiquitin-mediated pathways 通过泛素介导的途径重塑细胞膜
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.08.007
Anne-Claire Jacomin , Ivan Dikic

The dynamic process of membrane shaping and remodeling plays a vital role in cellular functions, with proteins and cellular membranes interacting intricately to adapt to various cellular needs and environmental cues. Ubiquitination—a posttranslational modification—was shown to be essential in regulating membrane structure and shape. It influences virtually all pathways relying on cellular membranes, such as endocytosis and autophagy by directing protein degradation, sorting, and oligomerization. Ubiquitin is mostly known as a protein modifier; however, it was reported that ubiquitin and ubiquitin-like proteins can associate directly with lipids, affecting membrane curvature and dynamics. In this review, we summarize some of the current knowledge on ubiquitin-mediated membrane remodeling in the context of endocytosis, autophagy, and ER-phagy.

膜塑形和重塑的动态过程在细胞功能中起着至关重要的作用,蛋白质和细胞膜错综复杂地相互作用,以适应各种细胞需求和环境线索。研究表明,泛素化--一种翻译后修饰--对调节膜结构和形状至关重要。它通过引导蛋白质降解、分类和寡聚化,影响着几乎所有依赖细胞膜的途径,如内吞和自噬。众所周知,泛素主要是一种蛋白质修饰剂;但有报道称,泛素和泛素样蛋白可直接与脂质结合,影响膜的曲率和动态。在这篇综述中,我们总结了目前关于泛素介导的膜重塑在内吞、自噬和ER-吞噬方面的一些知识。
{"title":"Membrane remodeling via ubiquitin-mediated pathways","authors":"Anne-Claire Jacomin ,&nbsp;Ivan Dikic","doi":"10.1016/j.chembiol.2024.08.007","DOIUrl":"10.1016/j.chembiol.2024.08.007","url":null,"abstract":"<div><p>The dynamic process of membrane shaping and remodeling plays a vital role in cellular functions, with proteins and cellular membranes interacting intricately to adapt to various cellular needs and environmental cues. Ubiquitination—a posttranslational modification—was shown to be essential in regulating membrane structure and shape. It influences virtually all pathways relying on cellular membranes, such as endocytosis and autophagy by directing protein degradation, sorting, and oligomerization. Ubiquitin is mostly known as a protein modifier; however, it was reported that ubiquitin and ubiquitin-like proteins can associate directly with lipids, affecting membrane curvature and dynamics. In this review, we summarize some of the current knowledge on ubiquitin-mediated membrane remodeling in the context of endocytosis, autophagy, and ER-phagy.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1627-1635"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624003568/pdfft?md5=ece0af39be652dce7a41d4b687f8ec63&pid=1-s2.0-S2451945624003568-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The hydrophobicity of the CARD8 N-terminus tunes inflammasome activation CARD8 N 端疏水性可调节炎症小体的激活
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.06.004

Mounting evidence indicates that proteotoxic stress is a primary activator of the CARD8 inflammasome, but the complete array of signals that control this inflammasome have not yet been established. Notably, we recently discovered that several hydrophobic radical-trapping antioxidants (RTAs), including JSH-23, potentiate CARD8 inflammasome activation through an unknown mechanism. Here, we report that these RTAs directly alkylate several cysteine residues in the N-terminal disordered region of CARD8. These hydrophobic modifications destabilize the repressive CARD8 N-terminal fragment and accelerate its proteasome-mediated degradation, thereby releasing the inflammatory CARD8 C-terminal fragment from autoinhibition. Consistently, we also found that unrelated (non-RTA) hydrophobic electrophiles as well as genetic mutation of the CARD8 cysteine residues to isoleucines similarly potentiate inflammasome activation. Overall, our results not only provide further evidence that protein folding stress is a key CARD8 inflammasome-activating signal, but also indicate that the N-terminal cysteines can play key roles in tuning the response to this stress.

越来越多的证据表明,蛋白毒性应激是 CARD8 炎症小体的主要激活剂,但控制 CARD8 炎症小体的信号阵列却很完整。
{"title":"The hydrophobicity of the CARD8 N-terminus tunes inflammasome activation","authors":"","doi":"10.1016/j.chembiol.2024.06.004","DOIUrl":"10.1016/j.chembiol.2024.06.004","url":null,"abstract":"<div><p><span>Mounting evidence indicates that proteotoxic stress is a primary activator of the CARD8 inflammasome<span>, but the complete array of signals that control this inflammasome<span> have not yet been established. Notably, we recently discovered that several hydrophobic radical-trapping antioxidants (RTAs), including JSH-23, potentiate CARD8 inflammasome<span> activation through an unknown mechanism. Here, we report that these RTAs directly alkylate several cysteine residues in the N-terminal disordered region of CARD8. These hydrophobic modifications destabilize the repressive CARD8 N-terminal fragment and accelerate its proteasome-mediated degradation, thereby releasing the inflammatory CARD8 C-terminal fragment from autoinhibition. Consistently, we also found that unrelated (non-RTA) hydrophobic </span></span></span></span>electrophiles<span><span> as well as genetic mutation<span> of the CARD8 cysteine residues to isoleucines similarly potentiate inflammasome activation. Overall, our results not only provide further evidence that </span></span>protein folding stress is a key CARD8 inflammasome-activating signal, but also indicate that the N-terminal cysteines can play key roles in tuning the response to this stress.</span></p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1699-1713.e8"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets 混合烷基/芳基膦酸盐将代谢丝氨酸水解酶确定为抗疟靶标
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.07.006
John M. Bennett , Sunil K. Narwal , Stephanie Kabeche , Daniel Abegg , Vandana Thathy , Fiona Hackett , Tomas Yeo , Veronica L. Li , Ryan Muir , Franco Faucher , Scott Lovell , Michael J. Blackman , Alexander Adibekian , Ellen Yeh , David A. Fidock , Matthew Bogyo

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. Our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are promising, synthetically tractable antimalarials.

由恶性疟原虫引起的疟疾仍然是严重的健康负担。开发抗疟药物的一个主要障碍是寄生虫能够迅速产生抗药性。我们以前曾证明,天然产物柳氮磺吡啶 A(SalA)通过抑制多种脂质代谢丝氨酸水解酶有效杀死寄生虫,这种机制导致了较低的抗药性倾向。鉴于将天然产物用作治疗剂的难度,我们合成了一个小型的脂质混合烷基/芳基膦酸盐库,作为 SalA 的生物异构体。两种构型异构体表现出不同的抗寄生虫效力,从而确定了治疗相关靶点。活性化合物杀死寄生虫的机制不同于 SalA 和泛脂肪酶抑制剂奥利司他,而且与奥利司他具有协同杀虫作用。我们的化合物只能诱导微弱的抗药性,这归因于参与多药耐药性的单个蛋白质发生了突变。这些数据表明,混合烷基/芳基膦酸盐是一种前景广阔、可合成的抗疟药物。
{"title":"Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets","authors":"John M. Bennett ,&nbsp;Sunil K. Narwal ,&nbsp;Stephanie Kabeche ,&nbsp;Daniel Abegg ,&nbsp;Vandana Thathy ,&nbsp;Fiona Hackett ,&nbsp;Tomas Yeo ,&nbsp;Veronica L. Li ,&nbsp;Ryan Muir ,&nbsp;Franco Faucher ,&nbsp;Scott Lovell ,&nbsp;Michael J. Blackman ,&nbsp;Alexander Adibekian ,&nbsp;Ellen Yeh ,&nbsp;David A. Fidock ,&nbsp;Matthew Bogyo","doi":"10.1016/j.chembiol.2024.07.006","DOIUrl":"10.1016/j.chembiol.2024.07.006","url":null,"abstract":"<div><p>Malaria, caused by <em>Plasmodium falciparum,</em> remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. Our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are promising, synthetically tractable antimalarials.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1714-1728.e10"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chemoproteomics reveals immunogenic and tumor-associated cell surface substrates of ectokinase CK2α 化学蛋白质组学揭示了外激酶 CK2α 的免疫原性和肿瘤相关细胞表面底物
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.07.018
Corleone S. Delaveris , Sophie Kong , Jeff Glasgow , Rita P. Loudermilk , Lisa L. Kirkemo , Fangzhu Zhao , Fernando Salangsang , Paul Phojanakong , Juan Antonio Camara Serrano , Veronica Steri , James A. Wells

Foreign epitopes for immune recognition provide the basis of anticancer immunity. Due to the high concentration of extracellular adenosine triphosphate in the tumor microenvironment, we hypothesized that extracellular kinases (ectokinases) could have dysregulated activity and introduce aberrant phosphorylation sites on cell surface proteins. We engineered a cell-tethered version of the extracellular kinase CK2α, demonstrated it was active on cells under tumor-relevant conditions, and profiled its substrate scope using a chemoproteomic workflow. We then demonstrated that mice developed polyreactive antisera in response to syngeneic tumor cells that had been subjected to surface hyperphosphorylation with CK2α. Interestingly, these mice developed B cell and CD4+ T cell responses in response to these antigens but failed to develop a CD8+ T cell response. This work provides a workflow for probing the extracellular phosphoproteome and demonstrates that extracellular phosphoproteins are immunogenic even in a syngeneic system.

免疫识别的外来表位是抗癌免疫的基础。由于肿瘤微环境中存在高浓度的细胞外三磷酸腺苷,我们假设细胞外激酶(ectokinases)可能会出现活性失调,并在细胞表面蛋白上引入异常磷酸化位点。我们设计了细胞外激酶 CK2α 的细胞系留版本,证明它在肿瘤相关条件下对细胞具有活性,并利用化学蛋白组学工作流程分析了它的底物范围。我们随后证明,小鼠对表面被 CK2α 过度磷酸化的合成肿瘤细胞产生了多反应抗血清。有趣的是,这些小鼠对这些抗原产生了 B 细胞和 CD4+ T 细胞反应,但未能产生 CD8+ T 细胞反应。这项研究提供了一种探测细胞外磷酸化蛋白质组的工作流程,并证明细胞外磷酸化蛋白质即使在共生系统中也具有免疫原性。
{"title":"Chemoproteomics reveals immunogenic and tumor-associated cell surface substrates of ectokinase CK2α","authors":"Corleone S. Delaveris ,&nbsp;Sophie Kong ,&nbsp;Jeff Glasgow ,&nbsp;Rita P. Loudermilk ,&nbsp;Lisa L. Kirkemo ,&nbsp;Fangzhu Zhao ,&nbsp;Fernando Salangsang ,&nbsp;Paul Phojanakong ,&nbsp;Juan Antonio Camara Serrano ,&nbsp;Veronica Steri ,&nbsp;James A. Wells","doi":"10.1016/j.chembiol.2024.07.018","DOIUrl":"10.1016/j.chembiol.2024.07.018","url":null,"abstract":"<div><p>Foreign epitopes for immune recognition provide the basis of anticancer immunity. Due to the high concentration of extracellular adenosine triphosphate in the tumor microenvironment, we hypothesized that extracellular kinases (ectokinases) could have dysregulated activity and introduce aberrant phosphorylation sites on cell surface proteins. We engineered a cell-tethered version of the extracellular kinase CK2α, demonstrated it was active on cells under tumor-relevant conditions, and profiled its substrate scope using a chemoproteomic workflow. We then demonstrated that mice developed polyreactive antisera in response to syngeneic tumor cells that had been subjected to surface hyperphosphorylation with CK2α. Interestingly, these mice developed B cell and CD4<sup>+</sup> T cell responses in response to these antigens but failed to develop a CD8<sup>+</sup> T cell response. This work provides a workflow for probing the extracellular phosphoproteome and demonstrates that extracellular phosphoproteins are immunogenic even in a syngeneic system.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 9","pages":"Pages 1729-1739.e9"},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142023133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Insights into lysophosphatidylserine recognition and Gα12/13-coupling specificity of P2Y10 透视 P2Y10 的溶血磷脂酰丝氨酸识别和 Gα12/13 偶联特异性
IF 8.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-11 DOI: 10.1016/j.chembiol.2024.08.005
Han Yin, Nozomi Kamakura, Yu Qian, Manae Tatsumi, Tatsuya Ikuta, Jiale Liang, Zhenmei Xu, Ruixue Xia, Anqi Zhang, Changyou Guo, Asuka Inoue, Yuanzheng He

The lysophosphatidylserine (LysoPS) receptor P2Y10, also known as LPS2, plays crucial roles in the regulation of immune responses and holds promise for the treatment of autoimmune diseases. Here, we report the cryoelectron microscopy (cryo-EM) structure of LysoPS-bound P2Y10 in complex with an engineered G13 heterotrimeric protein. The structure and a mutagenesis study highlight the predominant role of a comprehensive polar network in facilitating the binding and activation of the receptor by LysoPS. This interaction pattern is preserved in GPR174, but not in GPR34. Moreover, our structural study unveils the essential interactions that underlie the Gα13 engagement of P2Y10 and identifies key determinants for Gα12-vs.-Gα13-coupling selectivity, whose mutations selectively disrupt Gα12 engagement while preserving the intact coupling of Gα13. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα12/13 coupling specificity.

溶血磷脂酰丝氨酸(LysoPS)受体 P2Y10 又称 LPS2,在调节免疫反应中起着至关重要的作用,有望用于治疗自身免疫性疾病。在这里,我们报告了与 LysoPS 结合的 P2Y10 与工程化 G13 杂三聚体蛋白的冷冻电镜(cryo-EM)结构。该结构和诱变研究突出表明,一个全面的极性网络在促进 LysoPS 结合和激活受体方面起着主导作用。这种相互作用模式在 GPR174 中得以保留,但在 GPR34 中却没有保留。此外,我们的结构研究揭示了 P2Y10 的 Gα13 参与的基本相互作用,并确定了 Gα12 与 Gα13 偶联选择性的关键决定因素,其突变选择性地破坏了 Gα12 的参与,同时保留了 Gα13 的完整偶联。结合结构和功能研究,我们可以深入了解 LysoPS 识别和 Gα12/13 偶联特异性的分子机制。
{"title":"Insights into lysophosphatidylserine recognition and Gα12/13-coupling specificity of P2Y10","authors":"Han Yin, Nozomi Kamakura, Yu Qian, Manae Tatsumi, Tatsuya Ikuta, Jiale Liang, Zhenmei Xu, Ruixue Xia, Anqi Zhang, Changyou Guo, Asuka Inoue, Yuanzheng He","doi":"10.1016/j.chembiol.2024.08.005","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.08.005","url":null,"abstract":"<p>The lysophosphatidylserine (LysoPS) receptor P2Y10, also known as LPS<sub>2</sub>, plays crucial roles in the regulation of immune responses and holds promise for the treatment of autoimmune diseases. Here, we report the cryoelectron microscopy (cryo-EM) structure of LysoPS-bound P2Y10 in complex with an engineered G<sub>13</sub> heterotrimeric protein. The structure and a mutagenesis study highlight the predominant role of a comprehensive polar network in facilitating the binding and activation of the receptor by LysoPS. This interaction pattern is preserved in GPR174, but not in GPR34. Moreover, our structural study unveils the essential interactions that underlie the Gα<sub>13</sub> engagement of P2Y10 and identifies key determinants for Gα<sub>12</sub>-vs.-Gα<sub>13</sub>-coupling selectivity, whose mutations selectively disrupt Gα<sub>12</sub> engagement while preserving the intact coupling of Gα<sub>13</sub>. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα<sub>12/</sub><sub>13</sub> coupling specificity.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"8 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination 化学诱导 AIMP2-DX2 和 Siah1 之间的相互作用以增强泛素化
IF 8.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.chembiol.2024.08.004
Dae Gyu Kim, Minkyoung Kim, Ja-il Goo, Jiwon Kong, Dipesh S. Harmalkar, Qili Lu, Aneesh Sivaraman, Hossam Nada, Sreenivasulu Godesi, Hwayoung Lee, Mo Eun Song, Eunjoo Song, Kang-Hyun Han, Woojin Kim, Pilhan Kim, Won Jun Choi, Chang Hoon Lee, Sunkyung Lee, Yongseok Choi, Sunghoon Kim, Kyeong Lee

AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.

AIMP2-DX2(以下简称 DX2)是氨基酰-tRNA 合成酶相互作用多功能蛋白 2(AIMP2)的致癌变体,它能介导致癌因子与多种癌症相关因子的相互作用。降低 DX2 的水平可有效抑制肿瘤发生。我们以前曾报道 DX2 可通过 Siah1 介导的泛素化降解。在这项研究中,我们发现了一种化合物 SDL01,它能增强 DX2 与 Siah1 之间的相互作用,从而促进 DX2 的泛素依赖性降解。研究发现,SDL01 能与围绕 DX2 N 端柔性区和 GST 结构域的口袋结合,导致构象变化,从而稳定了 DX2 与 Siah1 的相互作用。我们的研究结果表明,蛋白质与蛋白质之间的相互作用(PPIs)可以通过化学诱导的构象变化来调节。
{"title":"Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination","authors":"Dae Gyu Kim, Minkyoung Kim, Ja-il Goo, Jiwon Kong, Dipesh S. Harmalkar, Qili Lu, Aneesh Sivaraman, Hossam Nada, Sreenivasulu Godesi, Hwayoung Lee, Mo Eun Song, Eunjoo Song, Kang-Hyun Han, Woojin Kim, Pilhan Kim, Won Jun Choi, Chang Hoon Lee, Sunkyung Lee, Yongseok Choi, Sunghoon Kim, Kyeong Lee","doi":"10.1016/j.chembiol.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.08.004","url":null,"abstract":"<p>AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the <em>N</em>-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"49 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer 化学筛选发现 PRMT5 是紫杉醇耐药三阴性乳腺癌的治疗漏洞
IF 8.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1016/j.chembiol.2024.08.003
KeJing Zhang, Juan Wei, SheYu Zhang, Liyan Fei, Lu Guo, Xueying Liu, YiShuai Ji, WenJun Chen, Felipe E. Ciamponi, WeiChang Chen, MengXi Li, Jie Zhai, Ting Fu, Katlin B. Massirer, Yang Yu, Mathieu Lupien, Yong Wei, Cheryl. H. Arrowsmith, Qin Wu, WeiHong Tan

Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.

紫杉醇耐药的三阴性乳腺癌(TNBC)仍然是最难治疗的乳腺癌之一。在这里,我们利用表观遗传化学探针筛选,发现了耐紫杉醇的 TNBC 细胞对蛋白精氨酸甲基转移酶(PRMTs)抑制的后天脆弱性。对细胞系和内部临床样本的分析表明,耐药细胞通过稳定有丝分裂染色质组装来逃避紫杉醇的杀伤。遗传或药物抑制 PRMT5 会改变 RNA 剪接,特别是极光激酶 B(AURKB)的内含子保留,导致蛋白质表达减少,最终导致紫杉醇耐药细胞的选择性有丝分裂灾难。此外,I型PRMT抑制与PRMT5抑制协同作用,通过增强对AURKB介导的有丝分裂信号通路的干扰,抑制耐药细胞的肿瘤生长。这些发现在由紫杉醇耐药的 TNBC 患者生成的患者衍生异种移植(PDX)模型中得到了充分再现,为在紫杉醇耐药的 TNBC 中靶向 PRMTs 提供了理论依据。
{"title":"A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer","authors":"KeJing Zhang, Juan Wei, SheYu Zhang, Liyan Fei, Lu Guo, Xueying Liu, YiShuai Ji, WenJun Chen, Felipe E. Ciamponi, WeiChang Chen, MengXi Li, Jie Zhai, Ting Fu, Katlin B. Massirer, Yang Yu, Mathieu Lupien, Yong Wei, Cheryl. H. Arrowsmith, Qin Wu, WeiHong Tan","doi":"10.1016/j.chembiol.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2024.08.003","url":null,"abstract":"<p>Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"7 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emerging biochemical, microbial and immunological evidence in the search for why HLA-B27 confers risk for spondyloarthritis. 寻找 HLA-B∗27 为何会导致脊柱关节炎风险的生化、微生物和免疫学证据。
IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.chembiol.2024.07.012
Eric M Brown, Phuong N U Nguyen, Ramnik J Xavier

The strong association of the human leukocyte antigen B27 alleles (HLA-B27) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B27 could trigger spondyloarthritis, with a focus on whether HLA-B27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9+ CD8+ T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.

人类白细胞抗原B∗27等位基因(HLA-B∗27)与脊柱关节炎及相关风湿病的密切关系一直令研究人员着迷,但其致病的确切机制却仍然难以捉摸。在这里,我们回顾了微生物组、免疫系统和神秘的 HLA-B∗27 之间的相互作用是如何诱发脊柱关节炎的,重点是 HLA-B∗27 是否会产生致关节炎肽。我们提出了 HLA-B∗27 蛋白结构的独特生化特性(尤其是其肽结合槽)可能决定其诱导病理 T 细胞反应倾向的机制。我们进一步提供了关于 TRBV9+ CD8+ T 细胞如何参与疾病过程以及 T 细胞的免疫代谢如何调节脊柱关节炎组织特异性炎症反应的新见解。最后,鉴于计算生物学、化学生物学、结构生物学和小分子疗法的最新进展,我们提出了可检验的模型,并建议在未来研究中解决这一问题的方法。
{"title":"Emerging biochemical, microbial and immunological evidence in the search for why HLA-B<sup>∗</sup>27 confers risk for spondyloarthritis.","authors":"Eric M Brown, Phuong N U Nguyen, Ramnik J Xavier","doi":"10.1016/j.chembiol.2024.07.012","DOIUrl":"10.1016/j.chembiol.2024.07.012","url":null,"abstract":"<p><p>The strong association of the human leukocyte antigen B<sup>∗</sup>27 alleles (HLA-B<sup>∗</sup>27) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B<sup>∗</sup>27 could trigger spondyloarthritis, with a focus on whether HLA-B<sup>∗</sup>27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B<sup>∗</sup>27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9<sup>+</sup> CD8<sup>+</sup> T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Cell Chemical Biology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1