Pub Date : 2024-09-19DOI: 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.
{"title":"Insights into bacterial metabolism from small RNAs","authors":"Kai Papenfort , 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}
Pub Date : 2024-09-19DOI: 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.
{"title":"Meet the authors: Lydia P. Tsamouri and Daniel A. Bachovchin","authors":"Lydia P. Tsamouri, 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}
Pub Date : 2024-09-19DOI: 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.
{"title":"Membrane remodeling via ubiquitin-mediated pathways","authors":"Anne-Claire Jacomin , 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}
Pub Date : 2024-09-19DOI: 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.
{"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}
Pub Date : 2024-09-19DOI: 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 , 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","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}
Pub Date : 2024-09-19DOI: 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 , 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","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}
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.
{"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}
Pub Date : 2024-09-10DOI: 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.
{"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}
Pub Date : 2024-09-03DOI: 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.
{"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}
Pub Date : 2024-08-20DOI: 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 B∗27 alleles (HLA-B∗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∗27 could trigger spondyloarthritis, with a focus on whether HLA-B∗27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B∗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+ 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}