Pub Date : 2025-11-20DOI: 10.1016/j.chembiol.2025.10.002
Ming Zhang , Meixia Chen , Peiyan Li , Jinrong Min
WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in MLL1-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (Kd = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation in vitro. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.
{"title":"Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression","authors":"Ming Zhang , Meixia Chen , Peiyan Li , Jinrong Min","doi":"10.1016/j.chembiol.2025.10.002","DOIUrl":"10.1016/j.chembiol.2025.10.002","url":null,"abstract":"<div><div>WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in <em>MLL1</em>-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (<em>K</em><sub>d</sub> = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation <em>in vitro</em>. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1353-1366.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367183","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.2025.10.011
Yi Yuan, Yaoyang Zhang
In an interview with Dr. Mishtu Dey, the editor-in-chief of Cell Chemical Biology, the authors of the research article entitled “TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics” share insights about their work and reflect on their scientific field and their journeys as researchers.
{"title":"Meet the authors: Yi Yuan and Yaoyang Zhang","authors":"Yi Yuan, Yaoyang Zhang","doi":"10.1016/j.chembiol.2025.10.011","DOIUrl":"10.1016/j.chembiol.2025.10.011","url":null,"abstract":"<div><div>In an interview with Dr. Mishtu Dey, the editor-in-chief of <em>Cell Chemical Biology</em>, the authors of the research article entitled “TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics” share insights about their work and reflect on their scientific field and their journeys as researchers.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1303-1304"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554787","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.2025.10.007
Yan Li , Lamei Xue , Feijie Wang , Yu Wang , Yujie Sun , Zhoumin Niu , Shengnan Liu , Ying Yan , Siyi Shen , Kuiliang Zhang , Chenzhipeng Nie , Mingcong Fan , Mei Ma , Yuting Wu , Binrui Yang , Jun Du , Ben Zhou , Duo Zhang , Billy K.C. Chow , Li Zhang , Li Wang
Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.
{"title":"Lactylation of mTOR enhances autophagy in skeletal muscle during exercise","authors":"Yan Li , Lamei Xue , Feijie Wang , Yu Wang , Yujie Sun , Zhoumin Niu , Shengnan Liu , Ying Yan , Siyi Shen , Kuiliang Zhang , Chenzhipeng Nie , Mingcong Fan , Mei Ma , Yuting Wu , Binrui Yang , Jun Du , Ben Zhou , Duo Zhang , Billy K.C. Chow , Li Zhang , Li Wang","doi":"10.1016/j.chembiol.2025.10.007","DOIUrl":"10.1016/j.chembiol.2025.10.007","url":null,"abstract":"<div><div>Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1367-1380.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485748","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.2025.10.008
Fabien Vincent , Davide Gianni
Phenotypic screens carried out with functional genomics or small molecules have led to novel biological insights, revealed previously unknown targets for drug discovery programs, and provided starting points for the development of first-in-class therapies. Despite being valuable research tools, genetic and compound screening also have significant limitations. This perspective aims to shed a light on those limitations and provide mitigation strategies when available, with a goal of helping phenotypic screening practitioners gain an understanding of how and when to best utilize either approach.
{"title":"The limitations of small molecule and genetic screening in phenotypic drug discovery","authors":"Fabien Vincent , Davide Gianni","doi":"10.1016/j.chembiol.2025.10.008","DOIUrl":"10.1016/j.chembiol.2025.10.008","url":null,"abstract":"<div><div>Phenotypic screens carried out with functional genomics or small molecules have led to novel biological insights, revealed previously unknown targets for drug discovery programs, and provided starting points for the development of first-in-class therapies. Despite being valuable research tools, genetic and compound screening also have significant limitations. This perspective aims to shed a light on those limitations and provide mitigation strategies when available, with a goal of helping phenotypic screening practitioners gain an understanding of how and when to best utilize either approach.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1310-1320"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492443","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.2025.10.005
Jingyu Feng , Jessica Page , Leeyup Chung , Zhigang He , Kuan Hong Wang
Cannabis-derived compounds, particularly the non-psychoactive cannabidiol (CBD), hold significant potential for pain management. However, CBD’s hydrophobicity limits systemic brain delivery, constraining both its therapeutic efficacy and mechanistic investigation. Here, we present an inclusion-complex-enhanced nano-micelle formulation (CBD-IN) that significantly improves systemic absorption and elevates brain CBD levels. A single dose of CBD-IN fully suppresses allodynia and hyperalgesia in a mouse model of neuropathic pain, without impairing normal sensorimotor or cognitive functions. This rapid and robust analgesic effect enables in-depth investigation of underlying neural mechanisms. Activity-dependent genetic mapping reveals that CBD-IN selectively reduces allodynia-associated neuronal activation across the somatosensory system. Complementary calcium imaging in spinal nociceptive and somatosensory corticospinal neurons further demonstrates pathophysiological state-dependent neural suppression by CBD. These results demonstrate that nano-formulated CBD delivers rapid and effective analgesia by selectively suppressing pathological hyperactivity throughout the somatosensory system, offering a promising therapeutic strategy for neuropathic pain and other disorders involving circuit-level disinhibition.
{"title":"Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol","authors":"Jingyu Feng , Jessica Page , Leeyup Chung , Zhigang He , Kuan Hong Wang","doi":"10.1016/j.chembiol.2025.10.005","DOIUrl":"10.1016/j.chembiol.2025.10.005","url":null,"abstract":"<div><div>Cannabis-derived compounds, particularly the non-psychoactive cannabidiol (CBD), hold significant potential for pain management. However, CBD’s hydrophobicity limits systemic brain delivery, constraining both its therapeutic efficacy and mechanistic investigation. Here, we present an inclusion-complex-enhanced nano-micelle formulation (CBD-IN) that significantly improves systemic absorption and elevates brain CBD levels. A single dose of CBD-IN fully suppresses allodynia and hyperalgesia in a mouse model of neuropathic pain, without impairing normal sensorimotor or cognitive functions. This rapid and robust analgesic effect enables in-depth investigation of underlying neural mechanisms. Activity-dependent genetic mapping reveals that CBD-IN selectively reduces allodynia-associated neuronal activation across the somatosensory system. Complementary calcium imaging in spinal nociceptive and somatosensory corticospinal neurons further demonstrates pathophysiological state-dependent neural suppression by CBD. These results demonstrate that nano-formulated CBD delivers rapid and effective analgesia by selectively suppressing pathological hyperactivity throughout the somatosensory system, offering a promising therapeutic strategy for neuropathic pain and other disorders involving circuit-level disinhibition.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1412-1428.e5"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454667","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.2025.10.006
Rachel P.M. Abrams , Rebecca G. Donahue , Jessica Ma , Ying Mao , Morgan E. Diolaiti , Alan Ashworth
Dysregulation of cysteine-dependent processes is implicated in many diseases, including cancer. Despite the importance of cysteine in crucial cellular functions, including protein synthesis, redox balance, and glutathione production, a lack of efficient assays to measure cellular cysteine has limited efforts to identify agents that affect physiological cysteine levels. We employed circular permutation to engineer a fluorescent sensor that changes conformation upon cysteine binding. Biochemical experiments showed that this sensor is selective for cysteine, operating in the 10 μM–10 mM range. To demonstrate the sensor’s applicability, we performed high-throughput screens for compounds that reduce cellular cysteine. Liquid chromatography of cell extracts validated the effect of two hit compounds, and mechanistic investigations showed that one was dependent on the anticancer target, xCT. Future application of this sensor in cell biology and drug discovery will advance understanding of cysteine metabolism and drive the development of therapeutics that restore cysteine homeostasis.
{"title":"An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels","authors":"Rachel P.M. Abrams , Rebecca G. Donahue , Jessica Ma , Ying Mao , Morgan E. Diolaiti , Alan Ashworth","doi":"10.1016/j.chembiol.2025.10.006","DOIUrl":"10.1016/j.chembiol.2025.10.006","url":null,"abstract":"<div><div>Dysregulation of cysteine-dependent processes is implicated in many diseases, including cancer. Despite the importance of cysteine in crucial cellular functions, including protein synthesis, redox balance, and glutathione production, a lack of efficient assays to measure cellular cysteine has limited efforts to identify agents that affect physiological cysteine levels. We employed circular permutation to engineer a fluorescent sensor that changes conformation upon cysteine binding. Biochemical experiments showed that this sensor is selective for cysteine, operating in the 10 μM–10 mM range. To demonstrate the sensor’s applicability, we performed high-throughput screens for compounds that reduce cellular cysteine. Liquid chromatography of cell extracts validated the effect of two hit compounds, and mechanistic investigations showed that one was dependent on the anticancer target, xCT. Future application of this sensor in cell biology and drug discovery will advance understanding of cysteine metabolism and drive the development of therapeutics that restore cysteine homeostasis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1381-1396.e8"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477871","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.2025.10.012
Dasa He , Guohong Hu
Aberrant Wnt signaling activation occurs in various cancers but has limited druggable targets. In this issue of Cell Chemical Biology, He et al.1 established a double death trap Wnt reporter system. Combined with genome-wide CRISPR screening, this approach identified STT3A as an essential Wnt signaling regulator with therapeutic potential.
{"title":"STT3A: Finding the sugar in Wnt signaling","authors":"Dasa He , Guohong Hu","doi":"10.1016/j.chembiol.2025.10.012","DOIUrl":"10.1016/j.chembiol.2025.10.012","url":null,"abstract":"<div><div>Aberrant Wnt signaling activation occurs in various cancers but has limited druggable targets. In this issue of <em>Cell Chemical Biology</em>, He et al.<span><span><sup>1</sup></span></span> established a double death trap Wnt reporter system. Combined with genome-wide CRISPR screening, this approach identified STT3A as an essential Wnt signaling regulator with therapeutic potential.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1308-1309"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554789","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.2025.10.001
Zhengjin He , Shishuang Chen , Jinlong Suo , Kai Xia , Mingxian Liu , Jingchuan Ma , Yankai Chu , Chao Wang , Yueru Xie , Wei Jiang , Hui Du , Shiyang Chen , Zhilei Zhou , Man Li , Qing Wei , Yun Zhao , Jianfeng Chen , Lin Li , Yi Zeng , Weiguo Zou , Hai Jiang
Abnormalities in the Wnt pathway are major drivers of cancer. RNF43 loss-of-function mutations are frequently detected in aggressive cancers lacking targeted therapies, underscoring the need to uncover key regulators and targets of this pathway. Using a double death trap (DDT) Wnt reporter and genome-wide CRISPR screen, we identified STT3A as an essential regulator of Wnt signaling. Genetic and pharmacological inhibition of STT3A suppressed aberrant Wnt activity caused by RNF43/ZNRF3 loss. Importantly, suppression of STT3A blocked the growth of RNF43-deficient cancer cell lines, patient-derived organoids, and spontaneous tumors. Mechanistically, STT3A regulates Wnt/β-catenin signaling via LRP6, but not LRP5. Glycosylation of LRP6 by STT3A is required for Wnt ligand binding. Notably, STT3A depletion displayed milder effects on bone homeostasis, as supported by phenotypes in STT3A-deficient patients. Together, this study established STT3A as a critical Wnt regulator through LRP6 glycosylation and a therapeutic target for RNF43-deficient cancers.
{"title":"STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency","authors":"Zhengjin He , Shishuang Chen , Jinlong Suo , Kai Xia , Mingxian Liu , Jingchuan Ma , Yankai Chu , Chao Wang , Yueru Xie , Wei Jiang , Hui Du , Shiyang Chen , Zhilei Zhou , Man Li , Qing Wei , Yun Zhao , Jianfeng Chen , Lin Li , Yi Zeng , Weiguo Zou , Hai Jiang","doi":"10.1016/j.chembiol.2025.10.001","DOIUrl":"10.1016/j.chembiol.2025.10.001","url":null,"abstract":"<div><div>Abnormalities in the Wnt pathway are major drivers of cancer. RNF43 loss-of-function mutations are frequently detected in aggressive cancers lacking targeted therapies, underscoring the need to uncover key regulators and targets of this pathway. Using a double death trap (DDT) Wnt reporter and genome-wide CRISPR screen, we identified STT3A as an essential regulator of Wnt signaling. Genetic and pharmacological inhibition of STT3A suppressed aberrant Wnt activity caused by RNF43/ZNRF3 loss. Importantly, suppression of STT3A blocked the growth of RNF43-deficient cancer cell lines, patient-derived organoids, and spontaneous tumors. Mechanistically, STT3A regulates Wnt/β-catenin signaling via LRP6, but not LRP5. Glycosylation of LRP6 by STT3A is required for Wnt ligand binding. Notably, STT3A depletion displayed milder effects on bone homeostasis, as supported by phenotypes in STT3A-deficient patients. Together, this study established STT3A as a critical Wnt regulator through LRP6 glycosylation and a therapeutic target for RNF43-deficient cancers.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1321-1335.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353172","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.2025.10.003
Yi Yuan , Zhimin Xu , Chenfang Si , Zan Gao , Xiaosong Liu , Yamei Yuan , Daichao Xu , Bing Shan , Yaoyang Zhang
Stress granules (SGs) are stress-induced membraneless organelles whose dynamics are tightly regulated by protein interactions and modifications. However, whether SUMOylation directly targets SG core proteins G3BP1/2 and which ligase is involved remains unclear, partly due to their transient and membraneless nature. To investigate this SUMOylation and its ligase, we applied our low-concentration formaldehyde crosslinking (lcFAX) method to stabilize SGs and enhance analysis. Using lcFAX-MS, we identified TRIM28 as a previously undefined SG-associated protein and showed that it SUMOylates G3BP1 at K287 and G3BP2 at K281, establishing a critical mechanism regulating SG dynamics that ultimately impacts cellular ROS and apoptosis. In addition, lcFAX-seq provides insights into SG RNA composition. Altogether, our study uncovers an essential role for TRIM28-mediated SUMOylation in modulating SG dynamics. TRIM28 may act as a versatile regulator, and with the aid of lcFAX, this mechanism could be further explored across diverse membraneless organelles and regulatory pathways.
{"title":"TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics","authors":"Yi Yuan , Zhimin Xu , Chenfang Si , Zan Gao , Xiaosong Liu , Yamei Yuan , Daichao Xu , Bing Shan , Yaoyang Zhang","doi":"10.1016/j.chembiol.2025.10.003","DOIUrl":"10.1016/j.chembiol.2025.10.003","url":null,"abstract":"<div><div>Stress granules (SGs) are stress-induced membraneless organelles whose dynamics are tightly regulated by protein interactions and modifications. However, whether SUMOylation directly targets SG core proteins G3BP1/2 and which ligase is involved remains unclear, partly due to their transient and membraneless nature. To investigate this SUMOylation and its ligase, we applied our low-concentration formaldehyde crosslinking (lcFAX) method to stabilize SGs and enhance analysis. Using lcFAX-MS, we identified TRIM28 as a previously undefined SG-associated protein and showed that it SUMOylates G3BP1 at K287 and G3BP2 at K281, establishing a critical mechanism regulating SG dynamics that ultimately impacts cellular ROS and apoptosis. In addition, lcFAX-seq provides insights into SG RNA composition. Altogether, our study uncovers an essential role for TRIM28-mediated SUMOylation in modulating SG dynamics. TRIM28 may act as a versatile regulator, and with the aid of lcFAX, this mechanism could be further explored across diverse membraneless organelles and regulatory pathways.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1336-1352.e6"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442046","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.2025.10.004
Bin Wang , Shouqing Luo , Pengkai Sun
Mutant isocitrate dehydrogenases (IDH1/IDH2) catalyze the conversion of α-ketoglutarate (αKG) to D-2-hydroxyglutarate (D2HG), a hallmark of many lower-grade gliomas. Elevated D2HG levels promote tumorigenesis through epigenetic reprogramming and immunosuppressive mechanisms, although paradoxically, D2HG can also inhibit tumor growth. To explore D2HG’s biological functions, we developed genetically encoded D2HG biosensors (DHsers) based on the prokaryotic transcriptional regulator DhdR. Structural analysis of DhdR, including its apo form, D2HG-bound complex, and DNA-bound complex, revealed that D2HG binding induces DhdR conformational changes that regulate DNA interaction. Leveraging these insights, we engineered biosensors (DHsers) that detect a wide range of concentrations of D2HG (0.3–30 mM) with high sensitivity. We also established a standardized protocol for quantifying subcellular D2HG levels in living cells. Notably, STING activation promotes D2HG production, suggesting a role of D2HG in immune modulation. Our findings reveal D2HG-induced transcriptional regulation in prokaryotes, offering a platform for studying the role of D2HG in cellular metabolism and tumorigenesis.
{"title":"Development of D2HG biosensors inspired by the molecular mechanism of D2HG regulation of DhdR","authors":"Bin Wang , Shouqing Luo , Pengkai Sun","doi":"10.1016/j.chembiol.2025.10.004","DOIUrl":"10.1016/j.chembiol.2025.10.004","url":null,"abstract":"<div><div>Mutant isocitrate dehydrogenases (IDH1/IDH2) catalyze the conversion of α-ketoglutarate (αKG) to D-2-hydroxyglutarate (D2HG), a hallmark of many lower-grade gliomas. Elevated D2HG levels promote tumorigenesis through epigenetic reprogramming and immunosuppressive mechanisms, although paradoxically, D2HG can also inhibit tumor growth. To explore D2HG’s biological functions, we developed genetically encoded D2HG biosensors (DHsers) based on the prokaryotic transcriptional regulator DhdR. Structural analysis of DhdR, including its apo form, D2HG-bound complex, and DNA-bound complex, revealed that D2HG binding induces DhdR conformational changes that regulate DNA interaction. Leveraging these insights, we engineered biosensors (DHsers) that detect a wide range of concentrations of D2HG (0.3–30 mM) with high sensitivity. We also established a standardized protocol for quantifying subcellular D2HG levels in living cells. Notably, STING activation promotes D2HG production, suggesting a role of D2HG in immune modulation. Our findings reveal D2HG-induced transcriptional regulation in prokaryotes, offering a platform for studying the role of D2HG in cellular metabolism and tumorigenesis.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 11","pages":"Pages 1397-1411.e7"},"PeriodicalIF":7.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447868","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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