Cell Chemical Biology最新文献

{"title":"Plasmodium falciparum Hsp90 supports DNA replication","authors":"Gaini Ibrasheva,Yueqi Chen,Michael E. Chirgwin,Caitlyn J. Hughes,Michael C. Fitzgerald,Emily R. Derbyshire","doi":"10.1016/j.chembiol.2026.10.003","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.10.003","url":null,"abstract":"Plasmodium falciparum heat shock protein 90 (PfHsp90) is an attractive antimalarial target, but the molecular pathways dependent on its activity remain poorly understood. Here, we use two chemically distinct Hsp90 inhibitors, geldanamycin and XL888, to profile the PfHsp90-dependent proteome during the blood stage. We identify 131 proteins reduced in abundance following both treatments, 40% of which co-immunoprecipitate with PfHsp90. DNA replication emerges as the most enriched pathway, and PfHsp90 inhibition reduces parasite DNA content and nascent DNA synthesis during blood- and liver-stage development. Combining Hsp90 inhibition with inhibitors of DNA replication further produces synergistic antiparasitic activity. Together, these findings establish a functional connection between PfHsp90 and parasite DNA replication and define a network of conserved and Plasmodium-specific proteins dependent on Hsp90 activity.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"8 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149374894","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}

{"title":"Host specific sphingomyelin is critical for replication of diverse RNA viruses","authors":"Shuo Han,Xiaolei Ye,Jintong Yang,Xuefang Peng,Xiaming Jiang,Jin Li,Xiaojie Zheng,Xinchen Zhang,Yumin Zhang,Lingyu Zhang,Wei Wang,Jiaxin Li,Wenwen Xin,Xiaoai Zhang,Gengfu Xiao,Ke Peng,Leike Zhang,Xuguang Du,Lu Zhou,Wei Liu,Hao Li","doi":"10.1016/j.chembiol.2026.10.007","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.10.007","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"1 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149374848","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}

{"title":"The calcium signaling links to fungal pathogenicity by a dual-action regulator","authors":"Yuanyuan Wang,Yongqin Wu,Luyao Zhang,Jihong Liu,Shuai Liu,Ning Gao,Xinhua Huang,Wenwen Xue,Yutong Dong,Junyun Huang,Chunmei Ying,Lin Zhong,Xinying Xue,Changbin Chen","doi":"10.1016/j.chembiol.2026.10.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.10.001","url":null,"abstract":"Candida albicans is a clinically important opportunistic fungal pathogen with a strong capacity to sense and adapt to fluctuating host microenvironments. Although transcription factor Crz1 is well established as a central regulator of calcium (Ca2+) homeostasis, accumulating evidence points to the involvement of additional factors. Through a large-scale genetic screen, we identified transcription factor Cas5 as a previously unrecognized regulator of Ca2+ homeostasis in C. albicans. Mechanistically, Cas5 directly represses the expression of protein kinase Tpk1, thereby influencing the dephosphorylation, nuclear localization, and downstream signaling activity of Crz1 to maintain Ca2+ balance. Furthermore, we show that calcineurin-dependent virulence requires Cas5 independently of Crz1, addressing a long-standing gap in understanding calcineurin-mediated pathogenicity. Collectively, our findings identify Cas5 as a dual-functional regulator coordinating Ca2+ homeostasis and pathogenicity in C. albicans, advancing our understanding of into its survival and virulence strategies within the host.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"23 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149367995","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}

{"title":"Phase-separated SOX5 drives human cranial neural crest fate commitment.","authors":"Xiaochao Huang, Yi Zhong, Kun Wang, Yaoxiang Li, Li Du, Hanyi Chen, Jingfei Xiong, Hui Bao, Chenlu Wang, Haoyang Cai, Hao Yang, Weidong Tian, Shiqian Qi, Zhonghan Li","doi":"10.1016/j.chembiol.2026.10.002","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.10.002","url":null,"abstract":"<p><p>Defective development of multipotent cranial neural crest cells (CNCCs) underlies diverse human neurocristopathies; yet, the mechanisms governing human CNCC fate commitment remain elusive. Using a human pluripotent stem cell (hPSC)-derived CNCC model, we generate transcriptomic, chromatin-accessibility, and transcription-factor-wide (TFome) CRISPR screening datasets, identifying SOX5 as a molecular switch for human CNCC specification. SOX5 loss retains the cells in a precursor-like state and strongly compromises their progression toward migratory CNCCs. Mechanistically, SOX5 forms nuclear condensates with properties consistent with liquid-liquid phase separation (LLPS) and compartmentalizes active chromatin and their three-dimensional organization. Through a prion-like domain (PLD), SOX5 self-associates and assembles a multiprotein hub containing the chromatin factor KU80, promoting a pro-CNCC program including ZNF467, EGR1, and SOX11. Disrupting the PLD shifts condensates to a more liquid-like state and disrupts KU80 recruitment. These findings uncover an LLPS-associated mechanism in human CNCC fate control, shedding light into the molecular etiology of neurodevelopmental disorders.</p>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149357006","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}

{"title":"Shared α-helix chimeraffibodies enable linker-free bispecific protein design","authors":"Xiaohui Qiu,Xu Chen,Zekai Zeng,Yongxiao Li,Jianye Yuan,Chang Xu,Jiaqi Wang,Xinpei Wang,Ruizhi Lai,Youjian Zhou,Jinghuan Mao,Yiqi Wang,Qiankun Liao,Zhe Wang,Junqing Wang","doi":"10.1016/j.chembiol.2026.09.022","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.09.022","url":null,"abstract":"Small protein scaffolds enable precise targeting but often rely on flexible linkers that increase conformational heterogeneity and immunogenic liabilities. Here we develop Chimeraffibodies (CABs), a linker-free bispecific scaffold class that encodes interdomain geometry through seamless α-helix sharing. CABs are designed by AlphaSync, a structure-design framework that defines domain orientation through closed-form exhaustive local rigid-body superposition and ProteinMPNN-based sequence refinement. Using HER2-binding affibody and an albumin-binding domain, we generated 861CM, which preserved parental paratopes while enforcing a defined shared-helix architecture. Structural, biophysical and cellular analyses demonstrated stable assembly, cooperative target recruitment and retained affinity, with HSA binding of ∼14.3 pM and HER2 binding of 610 pM in the albumin-bound state. In vivo imaging revealed sustained tumor localization, reduced hepatic and renal background and improved organ-to-tumor contrast. CABs establish helix sharing as a geometry-encoded strategy for generating compact, homogeneous, and pharmacokinetically optimized bispecific proteins.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"4 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149248498","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}

{"title":"Genetic dissection of rapid proteolysis identifies TXNDC15 as a key factor of ERAD and lipid homeostasis","authors":"Yuyang Liu,Michelle Yinfei Yaochai,Shanshan Liu,Hanan Alwaseem,Kıvanç Birsoy","doi":"10.1016/j.chembiol.2026.09.021","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.09.021","url":null,"abstract":"Biological systems face a constantly changing environment and must swiftly respond to stimuli; yet how cells sense and adapt to environmental and physiological cues is incompletely understood. Short-lived proteins can be rapidly induced upon perturbation, enabling swift activation of adaptive cellular responses. Here, leveraging genome-wide data on protein-transcript correlation, we systematically searched for rapid proteolysis substrates whose abundance reflects the activity of the underlying proteolytic machinery. Focusing on the candidate substrate ABHD2, we performed CRISPR-based genetic screens to dissect its degradation. These screens identified TXNDC15 as an essential factor in MARCHF6-mediated ER-associated protein degradation (ERAD). Mechanistically, TXNDC15 supports substrate exit and degradation from the ER via a catalysis-independent mechanism. Loss of TXNDC15 remodels the ER proteome and lipid homeostasis. Together, our work defines a missing component of ERAD and provides a generalizable strategy to decode post-translational regulatory circuits.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"291 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149230086","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}

{"title":"Proteasome inhibition bidirectionally regulates ferroptosis sensitivity","authors":"Magdalena B. Murray,Rishi Upadhyay,Krystina J. Szylo,Aastha Gautam,Judith Goncalves,Giovanni Forcina,Ananya Vinayak,Onn Brandman,Scott J. Dixon","doi":"10.1016/j.chembiol.2026.09.020","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.09.020","url":null,"abstract":"Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. The proteasome is an essential multiprotein complex important for protein turnover. How proteasome function regulates ferroptosis is difficult to study given that proteasome inhibition causes apoptosis. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining small molecule cell death inducers, pathway-specific cell death inhibitors, and direct cell death imaging. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system xc− inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. These findings establish proteasome-mediated protein turnover as a context-dependent regulator of ferroptosis and identify protein synthesis and ATF4 as key determinants of GPX4 inhibitor sensitivity.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"1 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225961","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}

{"title":"Small-molecule modulation of VDAC enhances glucose-stimulated insulin secretion by promoting ATP flux","authors":"Kohichi Matsunaga,Kaori Honda,Muneeb Ali,Abdul Hameed,Ryota Inoue,Takahiro Tsuno,Tatsuya Kin,A. M. James Shapiro,Hideru Obinata,Yasumitsu Kondoh,Zaheer Ul-Haq,Hiroyuki Osada,Tetsuro Izumi,Jun Shirakawa","doi":"10.1016/j.chembiol.2026.09.019","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.09.019","url":null,"abstract":"Reduced insulin secretion by β cells is a pivotal factor in diabetes onset and progression. The small molecule NPD976 was identified as a potent insulin secretagogue using high-throughput chemical screening employing an insulin secretion assay system. Even part of the molecular structure of NPD976, designated as DPEU (N-[2-(3,4-dimethoxyphenyl)ethyl]urea), retains insulin secretagogue activity. DPEU enhances insulin secretion specifically under glucose stimulation in β cells derived from mice, rats, and humans. The compound localizes to mitochondria in a manner independent of high glucose stimulation. Biochemical analyses revealed that DPEU directly interacts with voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane, enhancing ATP efflux from mitochondria into the cytosol during glucose stimulation. To our knowledge, DPEU is a positive small-molecule modulator of VDAC function that promotes ATP flux in β cells through a mechanism distinct from the classical KATP or cAMP pathways. These findings identify VDAC as a potential target for enhancing insulin secretion.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"73 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221458","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}

{"title":"Selective USP32 inhibition reveals endosomal ubiquitin signaling and enables cell-permeable activity-based probes","authors":"Stephan Scherpe,Febe C. Vermue,Vito Pol,Raymond Kooij,Adán Pinto-Fernández,Rayman T.N. Tjokrodirijo,Darragh P. O’Brien,Iolanda Vendrell,Dharjath S. Hameed,Ilana Berlin,Peter A. van Veelen,Benedikt M. Kessler,Paul P. Geurink,Aysegul Sapmaz","doi":"10.1016/j.chembiol.2026.09.018","DOIUrl":"https://doi.org/10.1016/j.chembiol.2026.09.018","url":null,"abstract":"Deubiquitinating enzymes (DUBs) regulate ubiquitin signaling and are attractive therapeutic targets, but selective chemical tools remain available for only a limited number of family members. Here, we report Huib32, the first potent and selective covalent inhibitor of ubiquitin-specific protease 32 (USP32). Huib32 rapidly and selectively engages USP32 in vitro and in cells, recapitulating USP32 loss of function by enhancing substrate ubiquitination, disrupting endosomal organization, and defining an expanded network of USP32-regulated membrane trafficking proteins. Building on Huib32, we develop the first cell-permeable activity-based probes for USP32, enabling direct visualization of active USP32 in cells and selective proteomic enrichment of the enzyme. Together, these first-in-class chemical tools establish selective chemical targeting of USP32 as an approach to interrogate endosomal ubiquitin signaling and provide a foundation for therapeutic exploration in cancers and other diseases associated with endocytic trafficking.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"13 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218196","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}

{"title":"Lysine methylation as a bidirectional switch","authors":"Bao Quang Gia Le,&nbsp;Ana Villalobos Galindo,&nbsp;Monika Raj","doi":"10.1016/j.chembiol.2026.05.013","DOIUrl":"10.1016/j.chembiol.2026.05.013","url":null,"abstract":"<div><div>Lysine methylation is classically linked to chromatin, yet an expanding literature shows that methylation on non-histone proteins can directly program protein lifetime through the Ub-proteasome system (UPS). We define a lysine methylation bidirectional switch in which methyl marks can be wired to opposite outcomes, degradation (methyl-degrons) or stabilization (methyl-stabilizers) depending on interpreter availability, competitive occupancy, and post-translational modification (PTM) neighborhood context. We organize the field into two symmetric frameworks and, within each, distinguish direct mechanisms from reader-mediated mechanisms. Across curated examples, both Kme1 and Kme2 are bidirectional, enabling either fate depending on the wiring. However, Kme1 dominates the degron pathways, while Kme3 only supports stabilization. We highlight recurring modular architectures and extract hypothesis-generating features that bias methyl sites toward degron versus stabilizer functions. Finally, we outline chemical biology opportunities to read and program this bidirectional switch, including antibody-independent chemoproteomics, proximity approaches for targeted methyl-editing for degradation and/or stabilization.</div></div><div>Lysine methylation is classically linked to chromatin, yet an expanding literature shows that methylation on non-histone proteins can directly program protein lifetime through the Ub-proteasome system (UPS). We define a lysine methylation bidirectional switch in which methyl marks can be wired to opposite outcomes, degradation (methyl-degrons) or stabilization (methyl-stabilizers) depending on interpreter availability, competitive occupancy, and post-translational modification (PTM) neighborhood context. We organize the field into two symmetric frameworks and, within each, distinguish direct mechanisms from reader-mediated mechanisms. Across curated examples, both Kme1 and Kme2 are bidirectional, enabling either fate depending on the wiring. However, Kme1 dominates the degron pathways, while Kme3 only supports stabilization. We highlight recurring modular architectures and extract hypothesis-generating features that bias methyl sites toward degron versus stabilizer functions. Finally, we outline chemical biology opportunities to read and program this bidirectional switch, including antibody-independent chemoproteomics, proximity approaches for targeted methyl-editing for degradation and/or stabilization.</div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (185KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 10","pages":"Pages 1387-1403"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148314870","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}