Pub Date : 2026-10-20DOI: 10.1016/j.chembiol.2026.09.019
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
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.
{"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}
Pub Date : 2026-10-19DOI: 10.1016/j.chembiol.2026.09.018
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
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.
{"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}
Pub Date : 2026-10-15Epub Date: 2026-06-24DOI: 10.1016/j.chembiol.2026.05.013
Bao Quang Gia Le, Ana Villalobos Galindo, Monika Raj
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.
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.
{"title":"Lysine methylation as a bidirectional switch","authors":"Bao Quang Gia Le, Ana Villalobos Galindo, 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}
Pub Date : 2026-10-15Epub Date: 2026-07-13DOI: 10.1016/j.chembiol.2026.06.006
David Joseph Shirley, Euna Yoo
ISG15 represents a key ubiquitin-like modifier induced primarily by interferon signaling. ISG15 is synthesized as a precursor, processed to a mature form, and covalently conjugated to substrates through a dedicated E1-E2-E3 enzymatic cascade involving UBE1L, UBE2L6, and E3 ligases such as HERC5, TRIM25, and ARIH1. This modification is reversed by deISGylases, particularly the highly specific protease USP18, which also negatively regulates interferon signaling. ISGylation impacts diverse molecular and cellular processes, including protein stability and function, protein-protein interaction, autophagy, transcription/translation, DNA damage response, and innate immunity. Advances in chemical biology and mass spectrometry-based proteomics have enabled the characterization of enzymes involved in (de)ISGylation and mapping of ISGylated proteins and sites. Dysregulated ISGylation is implicated in cancer, infection, neurodegenerative disorders, and inflammatory diseases, underscoring its broad pathophysiological relevance.
ISG15 represents a key ubiquitin-like modifier induced primarily by interferon signaling. ISG15 is synthesized as a precursor, processed to a mature form, and covalently conjugated to substrates through a dedicated E1-E2-E3 enzymatic cascade involving UBE1L, UBE2L6, and E3 ligases such as HERC5, TRIM25, and ARIH1. This modification is reversed by deISGylases, particularly the highly specific protease USP18, which also negatively regulates interferon signaling. ISGylation impacts diverse molecular and cellular processes, including protein stability and function, protein-protein interaction, autophagy, transcription/translation, DNA damage response, and innate immunity. Advances in chemical biology and mass spectrometry-based proteomics have enabled the characterization of enzymes involved in (de)ISGylation and mapping of ISGylated proteins and sites. Dysregulated ISGylation is implicated in cancer, infection, neurodegenerative disorders, and inflammatory diseases, underscoring its broad pathophysiological relevance.
{"title":"Understanding protein ISGylation, a multifaceted posttranslational modification","authors":"David Joseph Shirley, Euna Yoo","doi":"10.1016/j.chembiol.2026.06.006","DOIUrl":"10.1016/j.chembiol.2026.06.006","url":null,"abstract":"<div><div>ISG15 represents a key ubiquitin-like modifier induced primarily by interferon signaling. ISG15 is synthesized as a precursor, processed to a mature form, and covalently conjugated to substrates through a dedicated E1-E2-E3 enzymatic cascade involving UBE1L, UBE2L6, and E3 ligases such as HERC5, TRIM25, and ARIH1. This modification is reversed by deISGylases, particularly the highly specific protease USP18, which also negatively regulates interferon signaling. ISGylation impacts diverse molecular and cellular processes, including protein stability and function, protein-protein interaction, autophagy, transcription/translation, DNA damage response, and innate immunity. Advances in chemical biology and mass spectrometry-based proteomics have enabled the characterization of enzymes involved in (de)ISGylation and mapping of ISGylated proteins and sites. Dysregulated ISGylation is implicated in cancer, infection, neurodegenerative disorders, and inflammatory diseases, underscoring its broad pathophysiological relevance.</div></div><div>ISG15 represents a key ubiquitin-like modifier induced primarily by interferon signaling. ISG15 is synthesized as a precursor, processed to a mature form, and covalently conjugated to substrates through a dedicated E1-E2-E3 enzymatic cascade involving UBE1L, UBE2L6, and E3 ligases such as HERC5, TRIM25, and ARIH1. This modification is reversed by deISGylases, particularly the highly specific protease USP18, which also negatively regulates interferon signaling. ISGylation impacts diverse molecular and cellular processes, including protein stability and function, protein-protein interaction, autophagy, transcription/translation, DNA damage response, and innate immunity. Advances in chemical biology and mass spectrometry-based proteomics have enabled the characterization of enzymes involved in (de)ISGylation and mapping of ISGylated proteins and sites. Dysregulated ISGylation is implicated in cancer, infection, neurodegenerative disorders, and inflammatory diseases, underscoring its broad pathophysiological relevance.</div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (101KB)</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 1459-1481"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434433","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 : 2026-10-15DOI: 10.1016/j.chembiol.2026.09.015
In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the review entitled “Arginine methylation in immunoregulation: mechanisms and therapeutic targeting” reflect on advances in their field, their scientific journeys, and the experiences that have shaped their research.
In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the review entitled “Arginine methylation in immunoregulation: mechanisms and therapeutic targeting” reflect on advances in their field, their scientific journeys, and the experiences that have shaped their research.
在接受《细胞化学生物学》（Cell Chemical Biology）科学编辑萨曼莎·纳尔逊（Samantha Nelson）的采访时，这篇题为“免疫调节中的精氨酸甲基化：机制和治疗靶向”的综述的作者反思了他们所在领域的进展、他们的科学旅程以及影响他们研究的经历。
{"title":"Meet the authors: Song-Iee Han and Akiyoshi Fukamizu","authors":"","doi":"10.1016/j.chembiol.2026.09.015","DOIUrl":"10.1016/j.chembiol.2026.09.015","url":null,"abstract":"<div><div>In an interview with Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the review entitled “Arginine methylation in immunoregulation: mechanisms and therapeutic targeting” reflect on advances in their field, their scientific journeys, and the experiences that have shaped their research.</div></div><div>In an interview with Samantha Nelson, a scientific editor of <em>Cell Chemical Biology</em>, the authors of the review entitled “Arginine methylation in immunoregulation: mechanisms and therapeutic targeting” reflect on advances in their field, their scientific journeys, and the experiences that have shaped their research.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 10","pages":"Pages 1346-1347"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173074","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 : 2026-10-15Epub Date: 2026-10-06DOI: 10.1016/j.chembiol.2026.09.005
Nicole S. Walker, James J. Galligan, Yael David, Anna Knörlein
Immune cells are highly metabolically active throughout their life cycle, leading to elevated levels of a variety of reactive metabolites including reactive oxygen species, sugars, and lipid peroxidation products. These molecules covalently modify proteins, resulting in post-translational non-enzymatic covalent modifications (NECMs). Similar to their enzymatic counterparts, NECMs impact proteins’ structure, stability, localization, function, and interactome, thereby shaping cellular behavior, providing an additional layer of regulation to leukocyte function. With increasing evidence linking metabolic dysregulation to dysfunction of immune cells, it is becoming critical to understand the role NECMs play in regulating immune cell fate. This review highlights recent advances in our understanding of NECMs in immune cell function, including their roles in inflammation and immune responses. We further discuss emerging chemical biology technologies to detect, interrogate, and manipulate these modifications while outlining key challenges that will shape future studies of non-enzymatic protein modifications in immune regulation.
Immune cells are highly metabolically active throughout their life cycle, leading to elevated levels of a variety of reactive metabolites including reactive oxygen species, sugars, and lipid peroxidation products. These molecules covalently modify proteins, resulting in post-translational non-enzymatic covalent modifications (NECMs). Similar to their enzymatic counterparts, NECMs impact proteins’ structure, stability, localization, function, and interactome, thereby shaping cellular behavior, providing an additional layer of regulation to leukocyte function. With increasing evidence linking metabolic dysregulation to dysfunction of immune cells, it is becoming critical to understand the role NECMs play in regulating immune cell fate. This review highlights recent advances in our understanding of NECMs in immune cell function, including their roles in inflammation and immune responses. We further discuss emerging chemical biology technologies to detect, interrogate, and manipulate these modifications while outlining key challenges that will shape future studies of non-enzymatic protein modifications in immune regulation.
{"title":"Non-enzymatic protein modifications at the interface of metabolism and immunity","authors":"Nicole S. Walker, James J. Galligan, Yael David, Anna Knörlein","doi":"10.1016/j.chembiol.2026.09.005","DOIUrl":"10.1016/j.chembiol.2026.09.005","url":null,"abstract":"<div><div>Immune cells are highly metabolically active throughout their life cycle, leading to elevated levels of a variety of reactive metabolites including reactive oxygen species, sugars, and lipid peroxidation products. These molecules covalently modify proteins, resulting in post-translational non-enzymatic covalent modifications (NECMs). Similar to their enzymatic counterparts, NECMs impact proteins’ structure, stability, localization, function, and interactome, thereby shaping cellular behavior, providing an additional layer of regulation to leukocyte function. With increasing evidence linking metabolic dysregulation to dysfunction of immune cells, it is becoming critical to understand the role NECMs play in regulating immune cell fate. This review highlights recent advances in our understanding of NECMs in immune cell function, including their roles in inflammation and immune responses. We further discuss emerging chemical biology technologies to detect, interrogate, and manipulate these modifications while outlining key challenges that will shape future studies of non-enzymatic protein modifications in immune regulation.</div></div><div>Immune cells are highly metabolically active throughout their life cycle, leading to elevated levels of a variety of reactive metabolites including reactive oxygen species, sugars, and lipid peroxidation products. These molecules covalently modify proteins, resulting in post-translational non-enzymatic covalent modifications (NECMs). Similar to their enzymatic counterparts, NECMs impact proteins’ structure, stability, localization, function, and interactome, thereby shaping cellular behavior, providing an additional layer of regulation to leukocyte function. With increasing evidence linking metabolic dysregulation to dysfunction of immune cells, it is becoming critical to understand the role NECMs play in regulating immune cell fate. This review highlights recent advances in our understanding of NECMs in immune cell function, including their roles in inflammation and immune responses. We further discuss emerging chemical biology technologies to detect, interrogate, and manipulate these modifications while outlining key challenges that will shape future studies of non-enzymatic protein modifications in immune regulation.</div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (141KB)</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 1482-1500"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092129","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 : 2026-10-15Epub Date: 2026-09-23DOI: 10.1016/j.chembiol.2026.08.016
Youjia Wang, Chu Wang
Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.
Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.
{"title":"Chemoproteomic profiling of itaconate-derived protein modifications","authors":"Youjia Wang, Chu Wang","doi":"10.1016/j.chembiol.2026.08.016","DOIUrl":"10.1016/j.chembiol.2026.08.016","url":null,"abstract":"<div><div>Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.</div></div><div>Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 10","pages":"Pages 1501-1516"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019681","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 : 2026-10-15Epub Date: 2026-09-29DOI: 10.1016/j.chembiol.2026.08.018
Ashleigh L. Dale, Melanie Y. White, Stuart J. Cordwell
Post-translational modifications (PTMs) provide molecular variety beyond the gene or amino acid codes. Diversity stems from a vast number of chemical species or physical changes that are regulated either enzymatically or non-enzymatically to provide transient or prolonged alterations to protein structure and function. Bacteria are wrongly considered “simple” due to their relatively small genomes; however, application of high-resolution methods in enrichment, identification, and quantitation by mass spectrometry (MS) has unleashed a plethora of site-specific PTM data unequivocally demonstrating that bacteria can undertake almost all modifications seen in eukaryotes, while also maintaining novel PTMs that occur specifically in these organisms. Despite this, our ability to exploit omics-level PTM data has not been comparable; determining site stoichiometry, understanding the roles conferred by PTMs, and characterizing the functions of identified PTM sites remain to be routinely achievable at scale. This review examines major PTMs and their importance in generating functional variations in bacterial proteins.
Post-translational modifications (PTMs) provide molecular variety beyond the gene or amino acid codes. Diversity stems from a vast number of chemical species or physical changes that are regulated either enzymatically or non-enzymatically to provide transient or prolonged alterations to protein structure and function. Bacteria are wrongly considered “simple” due to their relatively small genomes; however, application of high-resolution methods in enrichment, identification, and quantitation by mass spectrometry (MS) has unleashed a plethora of site-specific PTM data unequivocally demonstrating that bacteria can undertake almost all modifications seen in eukaryotes, while also maintaining novel PTMs that occur specifically in these organisms. Despite this, our ability to exploit omics-level PTM data has not been comparable; determining site stoichiometry, understanding the roles conferred by PTMs, and characterizing the functions of identified PTM sites remain to be routinely achievable at scale. This review examines major PTMs and their importance in generating functional variations in bacterial proteins.
{"title":"Post-translational modifications in bacteria: From identification to function","authors":"Ashleigh L. Dale, Melanie Y. White, Stuart J. Cordwell","doi":"10.1016/j.chembiol.2026.08.018","DOIUrl":"10.1016/j.chembiol.2026.08.018","url":null,"abstract":"<div><div>Post-translational modifications (PTMs) provide molecular variety beyond the gene or amino acid codes. Diversity stems from a vast number of chemical species or physical changes that are regulated either enzymatically or non-enzymatically to provide transient or prolonged alterations to protein structure and function. Bacteria are wrongly considered “simple” due to their relatively small genomes; however, application of high-resolution methods in enrichment, identification, and quantitation by mass spectrometry (MS) has unleashed a plethora of site-specific PTM data unequivocally demonstrating that bacteria can undertake almost all modifications seen in eukaryotes, while also maintaining novel PTMs that occur specifically in these organisms. Despite this, our ability to exploit omics-level PTM data has not been comparable; determining site stoichiometry, understanding the roles conferred by PTMs, and characterizing the functions of identified PTM sites remain to be routinely achievable at scale. This review examines major PTMs and their importance in generating functional variations in bacterial proteins.</div></div><div>Post-translational modifications (PTMs) provide molecular variety beyond the gene or amino acid codes. Diversity stems from a vast number of chemical species or physical changes that are regulated either enzymatically or non-enzymatically to provide transient or prolonged alterations to protein structure and function. Bacteria are wrongly considered “simple” due to their relatively small genomes; however, application of high-resolution methods in enrichment, identification, and quantitation by mass spectrometry (MS) has unleashed a plethora of site-specific PTM data unequivocally demonstrating that bacteria can undertake almost all modifications seen in eukaryotes, while also maintaining novel PTMs that occur specifically in these organisms. Despite this, our ability to exploit omics-level PTM data has not been comparable; determining site stoichiometry, understanding the roles conferred by PTMs, and characterizing the functions of identified PTM sites remain to be routinely achievable at scale. This review examines major PTMs and their importance in generating functional variations in bacterial proteins.</div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (132KB)</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 1517-1543"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070992","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}
Post-translational modifications (PTMs) are central regulators of immune cell function, linking extracellular signals to the regulation of intracellular gene expression. Among these, protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a key mechanism that connects epigenetic control with signal transduction. PRMTs modify both histone and non-histone substrates, thereby regulating chromatin accessibility, transcriptional programs, and immune signaling pathways. Recent studies have shown that arginine methylation modulates immune cell activation, differentiation, and effector functions, whereas its dysregulation contributes to tumor immune evasion and chronic inflammation. Notably, alterations in PRMT activity have been increasingly suggested in age-associated immune remodeling and inflammaging. In this review, we integrate current evidence showing how PRMT-mediated arginine methylation coordinates chromatin regulation, RNA metabolism, and immune signaling, and examine how these mechanisms shape immune homeostasis, tumor immunity, inflammaging, and opportunities for therapeutic intervention.
Post-translational modifications (PTMs) are central regulators of immune cell function, linking extracellular signals to the regulation of intracellular gene expression. Among these, protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a key mechanism that connects epigenetic control with signal transduction. PRMTs modify both histone and non-histone substrates, thereby regulating chromatin accessibility, transcriptional programs, and immune signaling pathways. Recent studies have shown that arginine methylation modulates immune cell activation, differentiation, and effector functions, whereas its dysregulation contributes to tumor immune evasion and chronic inflammation. Notably, alterations in PRMT activity have been increasingly suggested in age-associated immune remodeling and inflammaging. In this review, we integrate current evidence showing how PRMT-mediated arginine methylation coordinates chromatin regulation, RNA metabolism, and immune signaling, and examine how these mechanisms shape immune homeostasis, tumor immunity, inflammaging, and opportunities for therapeutic intervention.
{"title":"Arginine methylation in immunoregulation: Mechanisms and therapeutic targeting","authors":"Song-Iee Han, Sachiko Toma-Fukai, Jun-Dal Kim, Koichiro Kako, Hiroaki Daitoku, Akiyoshi Fukamizu","doi":"10.1016/j.chembiol.2026.09.003","DOIUrl":"10.1016/j.chembiol.2026.09.003","url":null,"abstract":"<div><div>Post-translational modifications (PTMs) are central regulators of immune cell function, linking extracellular signals to the regulation of intracellular gene expression. Among these, protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a key mechanism that connects epigenetic control with signal transduction. PRMTs modify both histone and non-histone substrates, thereby regulating chromatin accessibility, transcriptional programs, and immune signaling pathways. Recent studies have shown that arginine methylation modulates immune cell activation, differentiation, and effector functions, whereas its dysregulation contributes to tumor immune evasion and chronic inflammation. Notably, alterations in PRMT activity have been increasingly suggested in age-associated immune remodeling and inflammaging. In this review, we integrate current evidence showing how PRMT-mediated arginine methylation coordinates chromatin regulation, RNA metabolism, and immune signaling, and examine how these mechanisms shape immune homeostasis, tumor immunity, inflammaging, and opportunities for therapeutic intervention.</div></div><div>Post-translational modifications (PTMs) are central regulators of immune cell function, linking extracellular signals to the regulation of intracellular gene expression. Among these, protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a key mechanism that connects epigenetic control with signal transduction. PRMTs modify both histone and non-histone substrates, thereby regulating chromatin accessibility, transcriptional programs, and immune signaling pathways. Recent studies have shown that arginine methylation modulates immune cell activation, differentiation, and effector functions, whereas its dysregulation contributes to tumor immune evasion and chronic inflammation. Notably, alterations in PRMT activity have been increasingly suggested in age-associated immune remodeling and inflammaging. In this review, we integrate current evidence showing how PRMT-mediated arginine methylation coordinates chromatin regulation, RNA metabolism, and immune signaling, and examine how these mechanisms shape immune homeostasis, tumor immunity, inflammaging, and opportunities for therapeutic intervention.</div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (198KB)</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 1422-1442"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090235","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 : 2026-10-15DOI: 10.1016/j.chembiol.2026.08.015
Alexander R. Mikesell, Zachary T. Campbell
Endoplasmic-reticulum-associated ribosome quality control (ER-RQC) requires ubiquitin-fold modifier 1 (UFM1) for UFMylation of the ribosomal protein RPL26. In the August 6 issue of Molecular Cell, Mao et al.1 identify an ER-associated complex (UFSP2/ODR4) as critical for deUFMylation of RPL26 and uncover a critical physiologic role for UFSP2 in neuronal proteostasis.
Endoplasmic-reticulum-associated ribosome quality control (ER-RQC) requires ubiquitin-fold modifier 1 (UFM1) for UFMylation of the ribosomal protein RPL26. In the August 6 issue of Molecular Cell, Mao et al.1 identify an ER-associated complex (UFSP2/ODR4) as critical for deUFMylation of RPL26 and uncover a critical physiologic role for UFSP2 in neuronal proteostasis.
{"title":"Location, location, deUFMylation: Coordinating ribosome quality control at the ER","authors":"Alexander R. Mikesell, Zachary T. Campbell","doi":"10.1016/j.chembiol.2026.08.015","DOIUrl":"10.1016/j.chembiol.2026.08.015","url":null,"abstract":"<div><div>Endoplasmic-reticulum-associated ribosome quality control (ER-RQC) requires ubiquitin-fold modifier 1 (UFM1) for UFMylation of the ribosomal protein RPL26. In the August 6 issue of <em>Molecular Cell</em>, Mao et al.<span><span><sup>1</sup></span></span> identify an ER-associated complex (UFSP2/ODR4) as critical for deUFMylation of RPL26 and uncover a critical physiologic role for UFSP2 in neuronal proteostasis.</div></div><div>Endoplasmic-reticulum-associated ribosome quality control (ER-RQC) requires ubiquitin-fold modifier 1 (UFM1) for UFMylation of the ribosomal protein RPL26. In the August 6 issue of <em>Molecular Cell</em>, Mao et al.<span><span><sup>1</sup></span></span> identify an ER-associated complex (UFSP2/ODR4) as critical for deUFMylation of RPL26 and uncover a critical physiologic role for UFSP2 in neuronal proteostasis.</div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"33 10","pages":"Pages 1353-1355"},"PeriodicalIF":9.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173072","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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