Pub Date : 2026-01-06DOI: 10.1016/j.chembiol.2025.11.013
Deguang Liang, Xuejun Jiang
{"title":"Redundant or resilient? A systems view of ferroptosis surveillance mechanisms","authors":"Deguang Liang, Xuejun Jiang","doi":"10.1016/j.chembiol.2025.11.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2025.11.013","url":null,"abstract":"","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"41 1","pages":""},"PeriodicalIF":8.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903110","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.2025.11.008
Wyatt Paulishak , Jianen Lyu , Michael S. VanNieuwenhze , Laurence M. Wood
Targeted drug delivery is among the fastest growing fields in cancer therapy. Advances in delivery have resulted in developments like antibody-drug conjugates (ADCs) and drug-loaded nanoparticles. Delivery, however, is hampered by target resistance, induced immunosuppression, and low tumor penetration. Listeria monocytogenes (LM) is a Gram-positive intracellular bacterium being investigated in preclinical and clinical trials as a therapeutic cancer vaccine platform. However, limited work has explored LM as a cytotoxin delivery vehicle. Here, we show that LM can deliver cytotoxin cargo resulting in increased cytotoxicity in vitro and reduced tumor growth in vivo in a microsatellite-stable (MSS) colorectal cancer (CRC) model. LM delivery of saporin dramatically improved cytotoxicity over SN38/Dox-ADC cargo. Reduced MSS CRC tumor growth was dependent on LM-mediated delivery of saporin and correlated with high immune infiltration. These results demonstrate efficacious cytotoxin delivery using LM and establish precedent for LM as a delivery vehicle for cytotoxic agents.
{"title":"Bugs delivering drugs: Listeria monocytogenes-mediated cytotoxin delivery enhances anti-tumor activity in colorectal cancer","authors":"Wyatt Paulishak , Jianen Lyu , Michael S. VanNieuwenhze , Laurence M. Wood","doi":"10.1016/j.chembiol.2025.11.008","DOIUrl":"10.1016/j.chembiol.2025.11.008","url":null,"abstract":"<div><div>Targeted drug delivery is among the fastest growing fields in cancer therapy. Advances in delivery have resulted in developments like antibody-drug conjugates (ADCs) and drug-loaded nanoparticles. Delivery, however, is hampered by target resistance, induced immunosuppression, and low tumor penetration. <em>Listeria monocytogenes</em> (LM) is a Gram-positive intracellular bacterium being investigated in preclinical and clinical trials as a therapeutic cancer vaccine platform. However, limited work has explored LM as a cytotoxin delivery vehicle. Here, we show that LM can deliver cytotoxin cargo resulting in increased cytotoxicity <em>in vitro</em> and reduced tumor growth <em>in vivo</em> in a microsatellite-stable (MSS) colorectal cancer (CRC) model. LM delivery of saporin dramatically improved cytotoxicity over SN38/Dox-ADC cargo. Reduced MSS CRC tumor growth was dependent on LM-mediated delivery of saporin and correlated with high immune infiltration. These results demonstrate efficacious cytotoxin delivery using LM and establish precedent for LM as a delivery vehicle for cytotoxic agents.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1517-1531.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145729092","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.2025.11.012
Steeve Akumwami , Susan L. Ingram
Mu-opioid receptors (MORs) are expressed in brain and contribute to a complex array of advantageous and deleterious behaviors. In this issue of Cell Chemical Biology, Sanchez et al.1 report a genetically encoded pharmacological tool to probe spatiotemporal release of endogenous opioids and their actions at MORs across cell types and circuits.
{"title":"Deciphering the opioid code","authors":"Steeve Akumwami , Susan L. Ingram","doi":"10.1016/j.chembiol.2025.11.012","DOIUrl":"10.1016/j.chembiol.2025.11.012","url":null,"abstract":"<div><div>Mu-opioid receptors (MORs) are expressed in brain and contribute to a complex array of advantageous and deleterious behaviors. In this issue of <em>Cell Chemical Biology,</em> Sanchez et al.<span><span><sup>1</sup></span></span> report a genetically encoded pharmacological tool to probe spatiotemporal release of endogenous opioids and their actions at MORs across cell types and circuits.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1429-1431"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771230","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.2025.10.009
Yuan Li , Jiwei Qiu , Zhihong Liu , Huiwen Xiao , Bin Wang , Yanxi Dong , Yunong Xiao , Qi Wang , Jiali Dong , Ming Cui
Food as medicine shows promise for disease intervention or treatment. Here, we found phytate, an active ingredient of plant-based diets, exhibits properties in mitigating radiotherapy-related complications. Oral gavage of phytate restored hematogenic organ atrophy, elevated peripheral blood neutrophils and white blood cells, reduced inflammation, and improved gastrointestinal (GI) integrity in irradiated mice. Phytate intake modulated the gut microbiota, facilitating the colonization of symbiotic Parasutterella in GI tract, thus combating intestinal radiation toxicity. In vitro assays and untargeted metabolomics identified 3-phenyllactic acid (PLA) and N-acetyl-L-leucine (NL) as functional metabolites produced by Parasutterella. In vitro, ex vivo, and in vivo models showed that PLA induces M2-like polarization in macrophages, while NL reduced oxidative stress, both counteracting radiation toxicity and working synergistically. Our findings offer mechanistic insights into phytate for alleviating radiation-associated complications and suggest that Parasutterella and its metabolites might be employed as promising probiotics or postbiotics for cancer patients undergoing radiotherapy.
{"title":"Phytate enhances gut Parasutterella colonization to alleviate radiation injury","authors":"Yuan Li , Jiwei Qiu , Zhihong Liu , Huiwen Xiao , Bin Wang , Yanxi Dong , Yunong Xiao , Qi Wang , Jiali Dong , Ming Cui","doi":"10.1016/j.chembiol.2025.10.009","DOIUrl":"10.1016/j.chembiol.2025.10.009","url":null,"abstract":"<div><div>Food as medicine shows promise for disease intervention or treatment. Here, we found phytate, an active ingredient of plant-based diets, exhibits properties in mitigating radiotherapy-related complications. Oral gavage of phytate restored hematogenic organ atrophy, elevated peripheral blood neutrophils and white blood cells, reduced inflammation, and improved gastrointestinal (GI) integrity in irradiated mice. Phytate intake modulated the gut microbiota, facilitating the colonization of symbiotic <em>Parasutterella</em> in GI tract, thus combating intestinal radiation toxicity. <em>In vitro</em> assays and untargeted metabolomics identified 3-phenyllactic acid (PLA) and N-acetyl-L-leucine (NL) as functional metabolites produced by <em>Parasutterella</em>. <em>In vitro</em>, <em>ex vivo</em>, and <em>in vivo</em> models showed that PLA induces M2-like polarization in macrophages, while NL reduced oxidative stress, both counteracting radiation toxicity and working synergistically. Our findings offer mechanistic insights into phytate for alleviating radiation-associated complications and suggest that <em>Parasutterella</em> and its metabolites might be employed as promising probiotics or postbiotics for cancer patients undergoing radiotherapy.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1458-1472.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532057","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.2025.11.002
J. Sanchez , A. Bonifazi , S. Groom , M.O. Sambrook , G.A. Camacho-Hernandez , E.J. Kuijer , S. Karimi , K.U. Therese , M. Hauge Pedersen , C. Rauffenbart , M. Canals , A.H. Newman , C.P. Bailey , J.A. Javitch , J.R. Lane
Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered in vivo to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.
{"title":"Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists","authors":"J. Sanchez , A. Bonifazi , S. Groom , M.O. Sambrook , G.A. Camacho-Hernandez , E.J. Kuijer , S. Karimi , K.U. Therese , M. Hauge Pedersen , C. Rauffenbart , M. Canals , A.H. Newman , C.P. Bailey , J.A. Javitch , J.R. Lane","doi":"10.1016/j.chembiol.2025.11.002","DOIUrl":"10.1016/j.chembiol.2025.11.002","url":null,"abstract":"<div><div>Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered <em>in vivo</em> to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 12","pages":"Pages 1473-1485.e9"},"PeriodicalIF":7.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657817","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.2025.11.006
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}
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