Pub Date : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.006
Avik Basu , Yuan Tian , Sergei Kotelnikov , Gabriel M. Cohn , Sadhna Phanse , Dima Kozakov , Heng-Ye Man , Andrew Emili
To investigate the molecular basis of homeostatic synaptic plasticity, we adapted a photo-proximity labeling-based functional proteomics workflow to identify protein-protein interactions involving the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in live primary rat neurons. Using antibodies conjugated to a photoactivatable flavin-based catalyst, we demonstrated target selective biotinylation and recovery of AMPAR along with both well-described and previously unreported auxiliary proteins associated with neurotransmission. This resulted in the identification of the calcium sensor neuronal calcium sensor 1 (NCS1), which we validated and functionally characterized as a key regulator of homeostatic plasticity initiated via engagement with the calcium-permeable AMPARs.
{"title":"Photo-proximity labeling in live primary neurons identifies an AMPA-receptor signal transducer in homeostatic synaptic plasticity","authors":"Avik Basu , Yuan Tian , Sergei Kotelnikov , Gabriel M. Cohn , Sadhna Phanse , Dima Kozakov , Heng-Ye Man , Andrew Emili","doi":"10.1016/j.chembiol.2025.11.006","DOIUrl":"10.1016/j.chembiol.2025.11.006","url":null,"abstract":"<div><div>To investigate the molecular basis of homeostatic synaptic plasticity, we adapted a photo-proximity labeling-based functional proteomics workflow to identify protein-protein interactions involving the GluA1 subunit of <strong>α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid</strong> receptor (AMPAR) in live primary rat neurons. Using antibodies conjugated to a photoactivatable flavin-based catalyst, we demonstrated target selective biotinylation and recovery of AMPAR along with both well-described and previously unreported auxiliary proteins associated with neurotransmission. This resulted in the identification of the calcium sensor neuronal calcium sensor 1 (NCS1), which we validated and functionally characterized as a key regulator of homeostatic plasticity initiated via engagement with the calcium-permeable AMPARs.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1545-1553.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711061","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.007
Zara Bukhari , Li Gu , Anneroos E. Nederstigt , Logan J. Cope , Derek L. Bolhuis , Kim Harvey , Tristan Allen , Spencer Hill , Yujie Yang , Guy Lawson , Cai Lu , Tommy Tran , Leah Pineda , Leanne Low , Andrew Chiang , Jason Song , Michelle V. Fong , Vanessa M. Rangel , William K. Chan , Gary Kleiger , Joseph S. Harrison
Ubiquitin (Ub) is a protein post-translational modifier that controls proteostasis through mechanisms spanning transcription, translation, and protein degradation. Ub conjugation occurs through a cascade of three enzyme classes (E1, E2, and E3s) involving >1,000 proteins that regulate the ubiquitination of cellular proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized. Here, we develop highly selective and potent pan-UBE2D/UBCH5 inhibitors by targeting the RING- and backside-binding sites with engineered linked-domain proteins. In HeLa cells, these inhibitors phenocopy the knockdown of UBE2D by enhancing chemosensitivity to cisplatin. Whole-cell proteomics reveals that ∼20% of the identified proteins are more abundant, and most do not have altered mRNA levels, suggesting that their protein turnover is regulated by UBE2D. Enrichment analysis of the altered mRNAs indicates that the linked-domain proteins trigger the unfolded protein response. These precision tools will enable new studies probing UBE2D’s cellular roles and help to deconvolute complex Ub regulatory networks.
{"title":"Linked-domain inhibitors designed to block UBE2D induce the unfolded protein response","authors":"Zara Bukhari , Li Gu , Anneroos E. Nederstigt , Logan J. Cope , Derek L. Bolhuis , Kim Harvey , Tristan Allen , Spencer Hill , Yujie Yang , Guy Lawson , Cai Lu , Tommy Tran , Leah Pineda , Leanne Low , Andrew Chiang , Jason Song , Michelle V. Fong , Vanessa M. Rangel , William K. Chan , Gary Kleiger , Joseph S. Harrison","doi":"10.1016/j.chembiol.2025.11.007","DOIUrl":"10.1016/j.chembiol.2025.11.007","url":null,"abstract":"<div><div>Ubiquitin (Ub) is a protein post-translational modifier that controls proteostasis through mechanisms spanning transcription, translation, and protein degradation. Ub conjugation occurs through a cascade of three enzyme classes (E1, E2, and E3s) involving >1,000 proteins that regulate the ubiquitination of cellular proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized. Here, we develop highly selective and potent pan-UBE2D/UBCH5 inhibitors by targeting the RING- and backside-binding sites with engineered linked-domain proteins. In HeLa cells, these inhibitors phenocopy the knockdown of UBE2D by enhancing chemosensitivity to cisplatin. Whole-cell proteomics reveals that ∼20% of the identified proteins are more abundant, and most do not have altered mRNA levels, suggesting that their protein turnover is regulated by UBE2D. Enrichment analysis of the altered mRNAs indicates that the linked-domain proteins trigger the unfolded protein response. These precision tools will enable new studies probing UBE2D’s cellular roles and help to deconvolute complex Ub regulatory networks.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1532-1544.e7"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689178","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.005
Samantha Marglous , Aneesa Z. Bhakta , Kara M. Gillmann , J. Sebastian Temme , Naomi Yamamoto , Avery Tytla , Alexander J. Bahnick , Jae Hyung Sim , Jeffrey C. Gildersleeve
Glycans play critical roles in cellular processes and clinical applications, but they remain difficult to study due to a shortage of well-characterized anti-glycan reagents and high-throughput technologies for glycome profiling, especially ones capable of single-cell resolution. To meet these needs, we generated a database of 650 anti-glycan antibody sequences, recombinantly expressed a library of 154 antibodies, and extensively characterized their binding properties using glycan microarrays. In addition to providing valuable information and resources for the field, the sequence database and microarray data also enabled development of “Glycomic-seq” (Glycome profiling via multiplexed immunoglobulins combined with sequencing), a DNA-barcoded anti-glycan antibody platform that enables high-throughput, single-cell profiling of both RNA and cell-surface glycan expression. Using Glycomic-seq, we profiled two isogenic colorectal cancer cell lines. The results revealed various glycans associated with cancer stem cells and metastasis, demonstrating the power of integrating glycomic information with multi-omic efforts to discover biomarkers and therapeutic targets.
{"title":"Single-cell glycome and transcriptome profiling enabled by a library of anti-glycan antibodies","authors":"Samantha Marglous , Aneesa Z. Bhakta , Kara M. Gillmann , J. Sebastian Temme , Naomi Yamamoto , Avery Tytla , Alexander J. Bahnick , Jae Hyung Sim , Jeffrey C. Gildersleeve","doi":"10.1016/j.chembiol.2025.11.005","DOIUrl":"10.1016/j.chembiol.2025.11.005","url":null,"abstract":"<div><div>Glycans play critical roles in cellular processes and clinical applications, but they remain difficult to study due to a shortage of well-characterized anti-glycan reagents and high-throughput technologies for glycome profiling, especially ones capable of single-cell resolution. To meet these needs, we generated a database of 650 anti-glycan antibody sequences, recombinantly expressed a library of 154 antibodies, and extensively characterized their binding properties using glycan microarrays. In addition to providing valuable information and resources for the field, the sequence database and microarray data also enabled development of “Glycomic-seq” (Glycome profiling via multiplexed immunoglobulins combined with sequencing), a DNA-barcoded anti-glycan antibody platform that enables high-throughput, single-cell profiling of both RNA and cell-surface glycan expression. Using Glycomic-seq, we profiled two isogenic colorectal cancer cell lines. The results revealed various glycans associated with cancer stem cells and metastasis, demonstrating the power of integrating glycomic information with multi-omic efforts to discover biomarkers and therapeutic targets.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1554-1568.e8"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711062","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.003
Alison C. Mody , Daniel H. Ramirez , Christina M. Woo
O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential nucleocytoplasmic post-translational modification (PTM) installed on many substrates by a single O-GlcNAc transferase (OGT), although functional outcomes for most of these modifications are unknown. Induced proximity methods to write and erase PTMs from desired targets can accelerate functional annotation and identify therapeutic opportunities for PTMs like O-GlcNAc. Here, we report an induced-proximity method with a destabilized nanobody-OGT fusion and demonstrate its general utility for targeted protein O-GlcNAc against 21 substrates followed by annotation of the direct effects of O-GlcNAc on transcription factors in cells. Deeper investigation of AP-1 transcriptional activation reveals an inhibitory nutrient-sensing event regulated by O-GlcNAc on transcription factors c-Fos and c-Jun. Collectively, these data illustrate the rapid investigation of O-GlcNAc functions in cells enabled by a generalizable induced proximity method for targeted protein O-GlcNAc.
O-Linked β- n -乙酰氨基葡萄糖（O-GlcNAc）是一种必要的核胞质翻译后修饰（PTM），通过单个O-GlcNAc转移酶（OGT）安装在许多底物上，尽管大多数这些修饰的功能结果尚不清楚。诱导接近方法从期望的靶标上写入和擦除PTMs可以加速功能注释，并确定PTMs如O-GlcNAc的治疗机会。在这里，我们报告了一种不稳定纳米体- ogt融合的诱导接近方法，并证明了其针对21种底物的靶向蛋白O-GlcNAc的一般效用，随后注释了O-GlcNAc对细胞中转录因子的直接影响。对AP-1转录激活的深入研究揭示了O-GlcNAc对转录因子c-Fos和c-Jun的抑制营养感应事件。总的来说，这些数据说明了通过靶向蛋白O-GlcNAc的通用诱导接近方法可以快速研究细胞中的O-GlcNAc功能。
{"title":"Targeted protein O-GlcNAc reveals transcriptional functions for O-GlcNAc","authors":"Alison C. Mody , Daniel H. Ramirez , Christina M. Woo","doi":"10.1016/j.chembiol.2025.11.003","DOIUrl":"10.1016/j.chembiol.2025.11.003","url":null,"abstract":"<div><div><em>O</em>-Linked β-<em>N</em>-acetylglucosamine (O-GlcNAc) is an essential nucleocytoplasmic post-translational modification (PTM) installed on many substrates by a single O-GlcNAc transferase (OGT), although functional outcomes for most of these modifications are unknown. Induced proximity methods to write and erase PTMs from desired targets can accelerate functional annotation and identify therapeutic opportunities for PTMs like O-GlcNAc. Here, we report an induced-proximity method with a destabilized nanobody-OGT fusion and demonstrate its general utility for targeted protein O-GlcNAc against 21 substrates followed by annotation of the direct effects of O-GlcNAc on transcription factors in cells. Deeper investigation of AP-1 transcriptional activation reveals an inhibitory nutrient-sensing event regulated by O-GlcNAc on transcription factors c-Fos and c-Jun. Collectively, these data illustrate the rapid investigation of O-GlcNAc functions in cells enabled by a generalizable induced proximity method for targeted protein O-GlcNAc.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1486-1502.e7"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712781","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.011
Linlin Wang , Sicong Yao , Yu-Hsuan Tsai
Proteins with noncanonical amino acids can serve as precision tools and therapeutics, but their creation is often inefficient. In a recent Nature publication, Iype et al.1 engineered bacteria to ferry designer amino acids as peptide cargos, overcoming a major uptake bottleneck and enabling robust, scalable incorporation under routine culture conditions.
{"title":"Peptide passports: Programmable import fuels novel protein building blocks","authors":"Linlin Wang , Sicong Yao , Yu-Hsuan Tsai","doi":"10.1016/j.chembiol.2025.11.011","DOIUrl":"10.1016/j.chembiol.2025.11.011","url":null,"abstract":"<div><div>Proteins with noncanonical amino acids can serve as precision tools and therapeutics, but their creation is often inefficient. In a recent <em>Nature</em> publication, Iype et al.<span><span><sup>1</sup></span></span> engineered bacteria to ferry designer amino acids as peptide cargos, overcoming a major uptake bottleneck and enabling robust, scalable incorporation under routine culture conditions.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1432-1435"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771229","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.010
Chih-Yao Chung , Kritarth Singh , Brigida R. Pinho , Jorge M.A. Oliveira , Michael R. Duchen
Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
{"title":"Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease","authors":"Chih-Yao Chung , Kritarth Singh , Brigida R. Pinho , Jorge M.A. Oliveira , Michael R. Duchen","doi":"10.1016/j.chembiol.2025.11.010","DOIUrl":"10.1016/j.chembiol.2025.11.010","url":null,"abstract":"<div><div>Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in <em>Science</em>,<span><span><sup>1</sup></span></span> Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1439-1441"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771268","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.009
Jingwei Liu , Xiaoyu Song , Liu Cao
PARP1 detects DNA damage and catalyzes PARylation of proteins to promote DNA damage response. In a study recently published by Nature Chemical Biology, Zhu et al.1 identify a new function for PARP1 in transcriptional restart by PARylation and stabilization of AFF1, which expands PARP1’s role to transcriptional recovery.
PARP1检测DNA损伤并催化蛋白质的PARylation以促进DNA损伤反应。在Nature Chemical Biology最近发表的一项研究中，Zhu等人1通过对AFF1的PARylation和稳定化发现了PARP1在转录重启中的新功能，这将PARP1的作用扩展到转录恢复。
{"title":"Transcriptional restart: A new role for PARylation in overcoming DNA damage","authors":"Jingwei Liu , Xiaoyu Song , Liu Cao","doi":"10.1016/j.chembiol.2025.11.009","DOIUrl":"10.1016/j.chembiol.2025.11.009","url":null,"abstract":"<div><div>PARP1 detects DNA damage and catalyzes PARylation of proteins to promote DNA damage response. In a study recently published by <em>Nature Chemical Biology</em>, Zhu et al.<span><span><sup>1</sup></span></span> identify a new function for PARP1 in transcriptional restart by PARylation and stabilization of AFF1, which expands PARP1’s role to transcriptional recovery.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1436-1438"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771743","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.001
Min Zhou , Ning Shi , Pilong Li
Multimerization and phase separation represent two paradigms for organizing receptor tyrosine kinases (RTKs). However, their functional distinctions from the perspective of biomolecular organization remain unclear. Here, we present CORdensate, a light-controllable condensation system combining two synergistic photoactuators: oligomeric Cry2 and heterodimeric LOVpep/ePDZ. Engineering single-chain photoswitches, we achieve four biomolecular organization patterns ranging from monomerization to phase separation. CORdensate exhibits constant assembly and disassembly kinetics. Applying CORdensate to mimic pathogenic RTK granules establishes the role of phase separation in activating ALK and RET. Moreover, assembling ALK and RET through varying organization patterns, we highlight the superior organizational ability of phase separation over multimerization. Additionally, CORdensate-based RTK granules suggest that phase separation broadly and robustly activates RTKs. This study introduces a optogenetic tool for investigating biomolecular condensation.
{"title":"Optogenetic control of biomolecular organization reveals distinct roles of phase separation in RTK signaling","authors":"Min Zhou , Ning Shi , Pilong Li","doi":"10.1016/j.chembiol.2025.11.001","DOIUrl":"10.1016/j.chembiol.2025.11.001","url":null,"abstract":"<div><div>Multimerization and phase separation represent two paradigms for organizing receptor tyrosine kinases (RTKs). However, their functional distinctions from the perspective of biomolecular organization remain unclear. Here, we present CORdensate, a light-controllable condensation system combining two synergistic photoactuators: oligomeric Cry2 and heterodimeric LOVpep/ePDZ. Engineering single-chain photoswitches, we achieve four biomolecular organization patterns ranging from monomerization to phase separation. CORdensate exhibits constant assembly and disassembly kinetics. Applying CORdensate to mimic pathogenic RTK granules establishes the role of phase separation in activating ALK and RET. Moreover, assembling ALK and RET through varying organization patterns, we highlight the superior organizational ability of phase separation over multimerization. Additionally, CORdensate-based RTK granules suggest that phase separation broadly and robustly activates RTKs. This study introduces a optogenetic tool for investigating biomolecular condensation.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1503-1516.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657865","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 : 2025-12-18DOI: 10.1016/j.chembiol.2025.11.004
Manijeh Khanmohammadi , Yasmin Mirzaalikhan , Sara Baratchi
The ability of innate immune cells to sense and respond to their physical environment is essential for regulating immune function. Macrophages, key players in inflammation, pathogen defense, and tissue repair, are influenced not only by biochemical cues but also by the mechanical properties of their microenvironment, including extracellular matrix stiffness, shear stress, and cyclic stretch. While the effects of soluble factors, such as cytokines on macrophage behavior are well characterized, the mechanisms underlying macrophage mechanotransduction remain poorly understood. This review synthesizes current understanding of how distinct mechanical forces shape macrophage activation, migration, polarization, and cytokine production. We also explore emerging insights into the roles of mechanosensitive ion channels (e.g., Piezo1, TRPV4), integrins, and cytoskeletal dynamics in transducing mechanical signals into pro- or anti-inflammatory responses. A deeper understanding of these pathways may uncover new therapeutic targets for treating cardiovascular diseases, including atherosclerosis.
{"title":"Immunity in motion: The role of mechanics in macrophage biology","authors":"Manijeh Khanmohammadi , Yasmin Mirzaalikhan , Sara Baratchi","doi":"10.1016/j.chembiol.2025.11.004","DOIUrl":"10.1016/j.chembiol.2025.11.004","url":null,"abstract":"<div><div>The ability of innate immune cells to sense and respond to their physical environment is essential for regulating immune function. Macrophages, key players in inflammation, pathogen defense, and tissue repair, are influenced not only by biochemical cues but also by the mechanical properties of their microenvironment, including extracellular matrix stiffness, shear stress, and cyclic stretch. While the effects of soluble factors, such as cytokines on macrophage behavior are well characterized, the mechanisms underlying macrophage mechanotransduction remain poorly understood. This review synthesizes current understanding of how distinct mechanical forces shape macrophage activation, migration, polarization, and cytokine production. We also explore emerging insights into the roles of mechanosensitive ion channels (e.g., Piezo1, TRPV4), integrins, and cytoskeletal dynamics in transducing mechanical signals into pro- or anti-inflammatory responses. A deeper understanding of these pathways may uncover new therapeutic targets for treating cardiovascular diseases, including atherosclerosis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1442-1457"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704154","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 : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.010
Hannah L. Baillie , Thomas A. Milne
In this issue of Cell Chemical Biology, Zhang et al.1 report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and in vivo antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.
{"title":"Small proteins with a big job: An EMBOW-derived microprotein targets WDR5-MLL1 and suppresses transcription in leukemia","authors":"Hannah L. Baillie , Thomas A. Milne","doi":"10.1016/j.chembiol.2025.10.010","DOIUrl":"10.1016/j.chembiol.2025.10.010","url":null,"abstract":"<div><div>In this issue of <em>Cell Chemical Biology</em>, Zhang et al.<span><span><sup>1</sup></span></span> report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and <em>in vivo</em> antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1305-1307"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554788","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}
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