Cell Chemical Biology最新文献_第7页

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

Cell Chemical Biology Pub Date : 2024-09-19 DOI: 10.1016/j.chembiol.2024.06.004

{"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>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.</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

Cell Chemical 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

{"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>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.</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

Cell Chemical 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

{"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>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.</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

Emerging biochemical, microbial and immunological evidence in the search for why HLA-B^∗27 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

Cell Chemical Biology Pub Date : 2024-08-20 DOI: 10.1016/j.chembiol.2024.07.012

Eric M Brown, Phuong N U Nguyen, Ramnik J Xavier

{"title":"Emerging biochemical, microbial and immunological evidence in the search for why HLA-B∗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":"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.","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

Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors 粘附 G 蛋白偶联受体中系留激动剂信号的异质性

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.03.004

引用次数: 0

Feel the breeze: Opening the therapeutic window with RIPTACs and induced proximity 感受微风利用 RIPTAC 和诱导接近打开治疗之窗

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.013

Kyle Mangano , Patrick Ryan Potts

引用次数: 0

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria 鉴定治疗疟疾的强效可逆哌啶羧酰胺类物种选择性口服活性蛋白酶体抑制剂

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.001

Aloysus Lawong , Suraksha Gahalawat , Sneha Ray , Nhi Ho , Yan Han , Kurt E. Ward , Xiaoyi Deng , Zhe Chen , Ashwani Kumar , Chao Xing , Varun Hosangadi , Kate J. Fairhurst , Kyuto Tashiro , Glen Liszczak , David M. Shackleford , Kasiram Katneni , Gong Chen , Jessica Saunders , Elly Crighton , Arturo Casas , Margaret A. Phillips

{"title":"Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria","authors":"Aloysus Lawong , Suraksha Gahalawat , Sneha Ray , Nhi Ho , Yan Han , Kurt E. Ward , Xiaoyi Deng , Zhe Chen , Ashwani Kumar , Chao Xing , Varun Hosangadi , Kate J. Fairhurst , Kyuto Tashiro , Glen Liszczak , David M. Shackleford , Kasiram Katneni , Gong Chen , Jessica Saunders , Elly Crighton , Arturo Casas , Margaret A. Phillips","doi":"10.1016/j.chembiol.2024.07.001","DOIUrl":"10.1016/j.chembiol.2024.07.001","url":null,"abstract":"<div>Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto β7. Inhibition of Pfβ5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the β5/β6/β3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1503-1517.e19"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2451945624002782/pdfft?md5=d0d63c5b95768cd07bd4ad29366f279e&pid=1-s2.0-S2451945624002782-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141795066","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

Precision epigenetic editing: Technological advances, enduring challenges, and therapeutic applications 精准表观遗传编辑：技术进步、持久挑战和治疗应用

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.007

Goldie V. Roth , Isabella R. Gengaro , Lei S. Qi

{"title":"Precision epigenetic editing: Technological advances, enduring challenges, and therapeutic applications","authors":"Goldie V. Roth , Isabella R. Gengaro , Lei S. Qi","doi":"10.1016/j.chembiol.2024.07.007","DOIUrl":"10.1016/j.chembiol.2024.07.007","url":null,"abstract":"<div>The epigenome is a complex framework through which gene expression is precisely and flexibly modulated to incorporate heritable memory and responses to environmental stimuli. It governs diverse cellular processes, including cell fate, disease, and aging. The need to understand this system and precisely control gene expression outputs for therapeutic purposes has precipitated the development of a diverse set of epigenetic editing tools. Here, we review the existing toolbox for targeted epigenetic editing, technical considerations of the current technologies, and opportunities for future development. We describe applications of therapeutic epigenetic editing and their potential for treating disease, with a discussion of ongoing delivery challenges that impede certain clinical interventions, particularly in the brain. With simultaneous advancements in available engineering tools and appropriate delivery technologies, we predict that epigenetic editing will increasingly cement itself as a powerful approach for safely treating a wide range of disorders in all tissues of the body.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1422-1446"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S245194562400309X/pdfft?md5=d1b75cb9f1e6f7156ed373d1c1fdaec2&pid=1-s2.0-S245194562400309X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918647","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

A versatile residue numbering scheme for Nav and Cav channels Nav 和 Cav 信道的通用残差编号方案

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.008

Xueqin Jin , Jian Huang , Huan Wang , Kan Wang , Nieng Yan

{"title":"A versatile residue numbering scheme for Nav and Cav channels","authors":"Xueqin Jin , Jian Huang , Huan Wang , Kan Wang , Nieng Yan","doi":"10.1016/j.chembiol.2024.07.008","DOIUrl":"10.1016/j.chembiol.2024.07.008","url":null,"abstract":"<div>Voltage-gated sodium (Nav) and calcium (Cav) channels are responsible for the initiation of electrical signals. They have long been targeted for the treatment of various diseases. The mounting number of cryoelectron microscopy (cryo-EM) structures for diverse subtypes of Nav and Cav channels from multiple organisms necessitates a generic residue numbering system to establish the structure-function relationship and to aid rational drug design or optimization. Here we suggest a structure-based residue numbering scheme, centering around the most conserved residues on each of the functional segments. We elaborate the generic numbers through illustrative examples, focusing on representative drug-binding sites of eukaryotic Nav and Cav channels. We also extend the numbering scheme to compare common disease mutations among different Nav subtypes. Application of the generic residue numbering scheme affords immediate insights into hotspots for pathogenic mutations and critical loci for drug binding and will facilitate drug discovery targeting Nav and Cav channels.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1394-1404"},"PeriodicalIF":6.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990567","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

Reflections from Nobel laureates in chemistry 诺贝尔化学奖获得者的思考

IF 6.6 1区生物学

Cell Chemical Biology Pub Date : 2024-08-15 DOI: 10.1016/j.chembiol.2024.07.016

Thomas R. Cech, Emmanuelle Charpentier, Aaron Ciechanover, Robert J. Lefkowitz, Kurt Wüthrich

引用次数: 0