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Rescuing T cells from stiff tumors 从僵硬的肿瘤中拯救 T 细胞
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.011
Mario J. Avellaneda , Michael Sixt
{"title":"Rescuing T cells from stiff tumors","authors":"Mario J. Avellaneda ,&nbsp;Michael Sixt","doi":"10.1016/j.chembiol.2024.06.011","DOIUrl":"10.1016/j.chembiol.2024.06.011","url":null,"abstract":"<div><p>In a recent issue of <em>Cell</em>, Zhang et al.<span><span><sup>1</sup></span></span> demonstrate that mechanical features of a solid tumor can drive T cells into dysfunctionality and identify pathways that revert this “exhausted” state.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1242-1243"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636603","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
STX-bpc: “Brightening” the path to neuronal inhibition STX-bpc："照亮 "神经元抑制之路
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.008
Jinxia Wan , Yulong Li
{"title":"STX-bpc: “Brightening” the path to neuronal inhibition","authors":"Jinxia Wan ,&nbsp;Yulong Li","doi":"10.1016/j.chembiol.2024.06.008","DOIUrl":"10.1016/j.chembiol.2024.06.008","url":null,"abstract":"<div><p>In this issue of <em>Cell Chemical Biology</em>, Elleman et al.<span><span><sup>1</sup></span></span> introduce a transformative chemical approach to control neuronal activity with high spatial and temporal resolution. The authors present STX-bpc, a potent neurotoxin that naturally inhibits voltage-gated sodium channels (Na<sub>V</sub>s), complementing available optogenetic methods for manipulating neuronal activity, cellular communication, and behavior.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1233-1235"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636733","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
CBLs downregulation foretells T cell ubiquitination leading to autoimmunity CBLs 下调预示着 T 细胞泛素化会导致自身免疫病
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.010
Aurobind Vidyarthi , Joe Craft
{"title":"CBLs downregulation foretells T cell ubiquitination leading to autoimmunity","authors":"Aurobind Vidyarthi ,&nbsp;Joe Craft","doi":"10.1016/j.chembiol.2024.06.010","DOIUrl":"10.1016/j.chembiol.2024.06.010","url":null,"abstract":"<div><p>In a study published in the July issue of <em>Immunity</em>, Li et al.<span><span><sup>1</sup></span></span> demonstrate that expression of the E3 ubiquitin ligases CBL and CBL-B is downregulated in Tfh cells in SLE with Tfh cell expansion and autoimmunity. This leads to reduced ubiquitination of the T cell costimulator ICOS which regulates proteostasis of the Tfh cell transcription factor BCL6 via chaperone-mediated autophagy.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1239-1241"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636769","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
Repurposing AS1411 for constructing ANM-PROTACs 重新利用 AS1411 构建 ANM-PROTAC
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.03.011
{"title":"Repurposing AS1411 for constructing ANM-PROTACs","authors":"","doi":"10.1016/j.chembiol.2024.03.011","DOIUrl":"10.1016/j.chembiol.2024.03.011","url":null,"abstract":"<div><p>Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for “undruggable” oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1290-1304.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140637617","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 sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened 一种甾醇类似物通过阻断平滑肌的胆固醇化抑制刺猬通路。
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.02.002
{"title":"A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened","authors":"","doi":"10.1016/j.chembiol.2024.02.002","DOIUrl":"10.1016/j.chembiol.2024.02.002","url":null,"abstract":"<div><p>The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1264-1276.e7"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S245194562400076X/pdfft?md5=9fca5500f416c04fdc676ebd0ebc03ad&pid=1-s2.0-S245194562400076X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038450","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
Development of covalent chemogenetic K2P channel activators 开发共价化学基因 K2P 通道激活剂
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.006
Parker E. Deal , Haerim Lee , Abhisek Mondal , Marco Lolicato , Philipe Ribeiro Furtado de Mendonça , Holly Black , Seil Jang , Xochina El-Hilali , Clifford Bryant , Ehud Y. Isacoff , Adam R. Renslo , Daniel L. Minor Jr.
{"title":"Development of covalent chemogenetic K2P channel activators","authors":"Parker E. Deal ,&nbsp;Haerim Lee ,&nbsp;Abhisek Mondal ,&nbsp;Marco Lolicato ,&nbsp;Philipe Ribeiro Furtado de Mendonça ,&nbsp;Holly Black ,&nbsp;Seil Jang ,&nbsp;Xochina El-Hilali ,&nbsp;Clifford Bryant ,&nbsp;Ehud Y. Isacoff ,&nbsp;Adam R. Renslo ,&nbsp;Daniel L. Minor Jr.","doi":"10.1016/j.chembiol.2024.06.006","DOIUrl":"10.1016/j.chembiol.2024.06.006","url":null,"abstract":"<div><p>K<sub>2P</sub> potassium channels regulate excitability by affecting cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. Despite their important roles in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine, the ability to control K<sub>2P</sub> function remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (covalent activation of TREK family K<sup>+</sup> channels to clamp membrane potential) that leverages the discovery of a K<sub>2P</sub> modulator pocket site that reacts with electrophile-bearing derivatives of a TREK subfamily small-molecule activator, ML335, to activate the channel irreversibly. We show that CATKLAMP can be used to probe fundamental aspects of K<sub>2P</sub> function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a means to alter K<sub>2P</sub> channel activity that should facilitate molecular and systems level studies of K<sub>2P</sub> function and enable the search for new K<sub>2P</sub> modulators.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1305-1323.e9"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141637808","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
Specificity profiling of deubiquitylases against endogenously generated ubiquitin-protein conjugates 去泛素酶对内源性泛素-蛋白质共轭物的特异性分析
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.05.001
{"title":"Specificity profiling of deubiquitylases against endogenously generated ubiquitin-protein conjugates","authors":"","doi":"10.1016/j.chembiol.2024.05.001","DOIUrl":"10.1016/j.chembiol.2024.05.001","url":null,"abstract":"<div><p>Deubiquitylating enzymes (DUBs) remove ubiquitin from proteins thereby regulating their stability or activity. Our understanding of DUB-substrate specificity is limited because DUBs are typically not compared to each other against many physiological substrates. By broadly inhibiting DUBs in <em>Xenopus</em> egg extract, we generated hundreds of ubiquitylated proteins and compared the ability of 30 DUBs to deubiquitylate them using quantitative proteomics. We identified five high-impact DUBs (USP7, USP9X, USP36, USP15, and USP24) that each reduced ubiquitylation of over 10% of the isolated proteins. Candidate substrates of high-impact DUBs showed substantial overlap and were enriched for disordered regions, suggesting this feature may promote substrate recognition. Other DUBs showed lower impact and non-overlapping specificity, targeting distinct non-disordered proteins including complexes such as the ribosome or the proteasome. Altogether our study identifies candidate DUB substrates and defines patterns of functional redundancy and specificity, revealing substrate characteristics that may influence DUB-substrate recognition.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1349-1362.e5"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159754","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
C646 degrades Exportin-1 to modulate p300 chromatin occupancy and function C646 降解 Exportin-1，从而调节 p300 染色质占有率和功能
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.05.016
{"title":"C646 degrades Exportin-1 to modulate p300 chromatin occupancy and function","authors":"","doi":"10.1016/j.chembiol.2024.05.016","DOIUrl":"10.1016/j.chembiol.2024.05.016","url":null,"abstract":"<div><p>Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1<sup>C528S</sup> drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1363-1372.e8"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444985","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
PARP trapping is governed by the PARP inhibitor dissociation rate constant PARP 诱捕受 PARP 抑制剂解离速率常数的控制
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2023.12.019
{"title":"PARP trapping is governed by the PARP inhibitor dissociation rate constant","authors":"","doi":"10.1016/j.chembiol.2023.12.019","DOIUrl":"10.1016/j.chembiol.2023.12.019","url":null,"abstract":"<div><p><span><span>Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of cancer drugs that enzymatically inhibit PARP activity at sites of </span>DNA<span><span> damage. Yet, PARPi function mainly by trapping PARP1 onto </span>DNA with a wide range of potency among the clinically relevant inhibitors. How PARPi trap and why some are better trappers remain unknown. Here, we show trapping occurs primarily through a kinetic phenomenon at sites of DNA damage that correlates with PARPi k</span></span><sub>off</sub>. Our results suggest PARP trapping is not the physical stalling of PARP1 on DNA, rather the high probability of PARP re-binding damaged DNA in the absence of other DNA-binding protein recruitment. These results clarify how PARPi trap, shed new light on how PARPi function, and describe how PARPi properties correlate to trapping potency.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1373-1382.e10"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139518924","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
Therapeutic potential of inhibiting the PI3Kγ complex for leukemia 抑制 PI3Kγ 复合物治疗白血病的潜力
IF 6.6 1区 生物学
Cell Chemical Biology Pub Date : 2024-07-18 DOI: 10.1016/j.chembiol.2024.06.009
Hanna Karvonen , Neil Vasan
{"title":"Therapeutic potential of inhibiting the PI3Kγ complex for leukemia","authors":"Hanna Karvonen ,&nbsp;Neil Vasan","doi":"10.1016/j.chembiol.2024.06.009","DOIUrl":"10.1016/j.chembiol.2024.06.009","url":null,"abstract":"<div><p>In their recent paper published in <em>Nature</em>, Luo et al.<span><span><sup>1</sup></span></span> investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 7","pages":"Pages 1244-1246"},"PeriodicalIF":6.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636604","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
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