Pub Date : 2026-01-27DOI: 10.1126/scisignal.adt3026
Naijiang Liu, Xiaojie Shi, Shao-Rui Chen, Hong Chen, Maria Daniela Santi, Dong Minh Phuong, Maria Fernanda Pessano Fialho, Tongxin Xie, Frederico Gleber-Netto, Rocco Latorre, Nigel W. Bunnett, Chi Viet, Moran Amit, Hui-Lin Pan, Yi Ye
Pain associated with oral cancer is debilitating. Opioids are the gold standard for cancer pain management, but tolerance and side effects limit their use. Epidermal growth factor receptor (EGFR) signaling is commonly amplified in oral tumors. Here, we found that EGFR activation contributed to both oral cancer pain and opioid tolerance by sensitizing trigeminal ganglion (TG) cells, the main sensory neurons innervating the face and mouth. EGFR ligands were secreted by oral squamous cell carcinoma (OSCC) cells and by peripheral glial cells cocultured with OSCC cells. In human OSCC and an orthotopic mouse model, EGFR was abundant in tumor-innervating TG nerves. Oral cancer pain and opioid tolerance in the mice were increased by EGFR ligands and reduced by EGFR inhibitors. In mice, the abundance of glutamate-type NMDA receptors (NMDARs) was also increased in both the TG and the brainstem. Upon activation by ligands or OSCC cell supernatant, EGFR phosphorylated the NMDAR subunit GluN2B, which increased electrical currents and sensitized pre- and postsynaptic NMDARs in the brainstem. This sensitization was also seen in the brainstems of mice receiving chronic morphine treatment and was mitigated by EGFR blockade. These findings suggest that EGFR-targeted cancer therapeutics may be repurposed to manage cancer pain and reduce opioid tolerance in patients with OSCC.
{"title":"EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer","authors":"Naijiang Liu, Xiaojie Shi, Shao-Rui Chen, Hong Chen, Maria Daniela Santi, Dong Minh Phuong, Maria Fernanda Pessano Fialho, Tongxin Xie, Frederico Gleber-Netto, Rocco Latorre, Nigel W. Bunnett, Chi Viet, Moran Amit, Hui-Lin Pan, Yi Ye","doi":"10.1126/scisignal.adt3026","DOIUrl":"10.1126/scisignal.adt3026","url":null,"abstract":"<div >Pain associated with oral cancer is debilitating. Opioids are the gold standard for cancer pain management, but tolerance and side effects limit their use. Epidermal growth factor receptor (EGFR) signaling is commonly amplified in oral tumors. Here, we found that EGFR activation contributed to both oral cancer pain and opioid tolerance by sensitizing trigeminal ganglion (TG) cells, the main sensory neurons innervating the face and mouth. EGFR ligands were secreted by oral squamous cell carcinoma (OSCC) cells and by peripheral glial cells cocultured with OSCC cells. In human OSCC and an orthotopic mouse model, EGFR was abundant in tumor-innervating TG nerves. Oral cancer pain and opioid tolerance in the mice were increased by EGFR ligands and reduced by EGFR inhibitors. In mice, the abundance of glutamate-type NMDA receptors (NMDARs) was also increased in both the TG and the brainstem. Upon activation by ligands or OSCC cell supernatant, EGFR phosphorylated the NMDAR subunit GluN2B, which increased electrical currents and sensitized pre- and postsynaptic NMDARs in the brainstem. This sensitization was also seen in the brainstems of mice receiving chronic morphine treatment and was mitigated by EGFR blockade. These findings suggest that EGFR-targeted cancer therapeutics may be repurposed to manage cancer pain and reduce opioid tolerance in patients with OSCC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 922","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049468","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 : 2026-01-27DOI: 10.1126/scisignal.aef7044
Wei Wong
A high-fat diet impairs the growth of a commensal that produces lipids with anti-obesogenic effects in mice.
高脂肪饮食会损害共生体的生长，共生体产生具有抗肥胖作用的脂质。
{"title":"A hostile environment for a commensal","authors":"Wei Wong","doi":"10.1126/scisignal.aef7044","DOIUrl":"10.1126/scisignal.aef7044","url":null,"abstract":"<div >A high-fat diet impairs the growth of a commensal that produces lipids with anti-obesogenic effects in mice.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 922","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049470","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 : 2026-01-20DOI: 10.1126/scisignal.aed6832
Neel H. Shah
The chemical reagent pervanadate is widely used to study phosphotyrosine signaling because it is a potent, irreversible inhibitor of protein tyrosine phosphatases that globally increases tyrosine phosphorylation across the proteome. In this issue of Science Signaling, Mulholland et al. show that pervanadate also modulates phosphotyrosine signaling by oxidizing specific cysteine residues on the tyrosine kinase SRC, thereby leading to hyperactivation of this ubiquitous signaling enzyme.
{"title":"Pervanadate: So much more than a protein tyrosine phosphatase inhibitor","authors":"Neel H. Shah","doi":"10.1126/scisignal.aed6832","DOIUrl":"10.1126/scisignal.aed6832","url":null,"abstract":"<div >The chemical reagent pervanadate is widely used to study phosphotyrosine signaling because it is a potent, irreversible inhibitor of protein tyrosine phosphatases that globally increases tyrosine phosphorylation across the proteome. In this issue of <i>Science Signaling</i>, Mulholland <i>et al.</i> show that pervanadate also modulates phosphotyrosine signaling by oxidizing specific cysteine residues on the tyrosine kinase SRC, thereby leading to hyperactivation of this ubiquitous signaling enzyme.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 921","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002612","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 : 2026-01-20DOI: 10.1126/scisignal.ady9437
Katie E. Mulholland, Maxime Bourguet, Nuo Cheng, Oisharja Rahman, Daria Ezeriņa, Leonard A. Daly, Tiffany Lai, Silvia Aldaz Casanova, Therese Featherston, Pau Creixell, Claire E. Eyers, Joris Messens, Patrick A. Eyers, Dominic P. Byrne, Hayley J. Sharpe
Dynamic regulation of protein tyrosine phosphorylation (pTyr) by kinases and phosphatases enables cells to sense and respond to environmental changes. The widely used chemical pervanadate induces the accumulation of pTyr in mammalian cell lines. This effect is primarily attributed to its inhibition of protein tyrosine phosphatases (PTPs), leading to the assertion that PTPs are master gatekeepers of intracellular pTyr homeostasis. Here, we used several approaches to reveal that pervanadate disrupted cellular redox homeostasis and directly activated tyrosine kinases of the SRC family through the oxidation of specific cysteine residues. Mass spectrometry and biophysical approaches showed that pervanadate-induced oxidation of cysteine-188 and cysteine-280 activated SRC by disrupting autoinhibitory intramolecular interactions between the catalytic domain and the SH2/SH3 domains and by impairing SH2 domain binding to phosphopeptides, including the regulatory carboxyl-terminal tail phosphotyrosine-530. Redox-sensitive cysteine residues were essential for SRC to promote the overgrowth of mouse fibroblasts. Our findings call for a reevaluation of pervanadate-based experiments and demonstrate that SRC cysteines control its oncogenic properties.
{"title":"Pervanadate-induced oxidation relieves autoinhibition of the protein tyrosine kinase SRC","authors":"Katie E. Mulholland, Maxime Bourguet, Nuo Cheng, Oisharja Rahman, Daria Ezeriņa, Leonard A. Daly, Tiffany Lai, Silvia Aldaz Casanova, Therese Featherston, Pau Creixell, Claire E. Eyers, Joris Messens, Patrick A. Eyers, Dominic P. Byrne, Hayley J. Sharpe","doi":"10.1126/scisignal.ady9437","DOIUrl":"10.1126/scisignal.ady9437","url":null,"abstract":"<div >Dynamic regulation of protein tyrosine phosphorylation (pTyr) by kinases and phosphatases enables cells to sense and respond to environmental changes. The widely used chemical pervanadate induces the accumulation of pTyr in mammalian cell lines. This effect is primarily attributed to its inhibition of protein tyrosine phosphatases (PTPs), leading to the assertion that PTPs are master gatekeepers of intracellular pTyr homeostasis. Here, we used several approaches to reveal that pervanadate disrupted cellular redox homeostasis and directly activated tyrosine kinases of the SRC family through the oxidation of specific cysteine residues. Mass spectrometry and biophysical approaches showed that pervanadate-induced oxidation of cysteine-188 and cysteine-280 activated SRC by disrupting autoinhibitory intramolecular interactions between the catalytic domain and the SH2/SH3 domains and by impairing SH2 domain binding to phosphopeptides, including the regulatory carboxyl-terminal tail phosphotyrosine-530. Redox-sensitive cysteine residues were essential for SRC to promote the overgrowth of mouse fibroblasts. Our findings call for a reevaluation of pervanadate-based experiments and demonstrate that SRC cysteines control its oncogenic properties.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 921","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002611","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 : 2026-01-20DOI: 10.1126/scisignal.ady2026
Philip A. Freund, Nicolas Panayotis, PingAn Yuanxiang, Sebastian Samer, Leilah Otikovs, Riki Kawaguchi, Juan Oses-Prieto, Talieh Zomorrodinia, Ida Rishal, Michaela Schweizer, Michael Tsoory, Katarzyna M. Grochowska, Anna Karpova, Alma L. Burlingame, Michael R. Kreutz, Mike Fainzilber
Axonal localization and local translation of mRNA encoding importin β1 are important for retrograde injury signaling and axonal growth. Here, we found that loss of importin β1 in axons through deletion of the mRNA’s 3′ untranslated region (3′UTR) caused a specific spatial memory deficit in mice. Electrophysiological analyses of hippocampal circuits revealed that mice expressing importin β1 transcripts lacking the 3′UTR (∆3′UTR) had impaired long-term potentiation (LTP) in presynaptic mossy fibers. Furthermore, mass spectrometry revealed an altered synaptic proteome and phosphoproteome, and sequencing of ribosome-associated RNAs showed suppression of locally translated presynaptic mRNAs in dentate gyrus neurons from mice expressing ∆3′UTR importin β1. This dysregulation was reflected in a reduction in the readily releasable pool of synaptic vesicles in mossy fiber synapses. Thus, axonal localization of importin β1–encoding mRNA is required to shape the presynapse, and disruption of this mechanism causes memory deficits.
{"title":"Subcellular depletion of importin β1 impairs presynaptic local translation and spatial memory","authors":"Philip A. Freund, Nicolas Panayotis, PingAn Yuanxiang, Sebastian Samer, Leilah Otikovs, Riki Kawaguchi, Juan Oses-Prieto, Talieh Zomorrodinia, Ida Rishal, Michaela Schweizer, Michael Tsoory, Katarzyna M. Grochowska, Anna Karpova, Alma L. Burlingame, Michael R. Kreutz, Mike Fainzilber","doi":"10.1126/scisignal.ady2026","DOIUrl":"10.1126/scisignal.ady2026","url":null,"abstract":"<div >Axonal localization and local translation of mRNA encoding importin β1 are important for retrograde injury signaling and axonal growth. Here, we found that loss of importin β1 in axons through deletion of the mRNA’s 3′ untranslated region (3′UTR) caused a specific spatial memory deficit in mice. Electrophysiological analyses of hippocampal circuits revealed that mice expressing importin β1 transcripts lacking the 3′UTR (∆3′UTR) had impaired long-term potentiation (LTP) in presynaptic mossy fibers. Furthermore, mass spectrometry revealed an altered synaptic proteome and phosphoproteome, and sequencing of ribosome-associated RNAs showed suppression of locally translated presynaptic mRNAs in dentate gyrus neurons from mice expressing ∆3′UTR importin β1. This dysregulation was reflected in a reduction in the readily releasable pool of synaptic vesicles in mossy fiber synapses. Thus, axonal localization of importin β1–encoding mRNA is required to shape the presynapse, and disruption of this mechanism causes memory deficits.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 921","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002610","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 : 2026-01-13DOI: 10.1126/scisignal.adw3709
Vera-Marie E. Dunlock, Sergi Regot
T cells achieve precise antigen discrimination by relying on the temporal stability of T cell receptor (TCR) interactions with antigens. Given that time is central to antigen discrimination, we used real-time, single-cell imaging in a controlled TCR-antigen system to characterize extracellular signal–regulated kinase (ERK) signaling dynamics as a function of antigen affinity to better understand the temporal patterns of signaling downstream of the TCR. We found that intermediate-affinity antigens elicited pulsatile ERK activity at different frequencies and that T cell activation correlated with the cumulative amount of ERK activity. Mechanistically, we found that the ERK pulsing frequency depended on the rate of activity of the Src family kinase LCK at the plasma membrane, whereas mitogen-activated protein kinase (MAPK) kinase (MEK) modulated the amplitude of ERK signaling. Moreover, we showed that ERK activity dynamics in T cells depended on members of two upstream MAP3K groups: mixed lineage kinases (MLKs) and RAFs, which played distinct roles promoting or sustaining the formation of upstream signaling condensates containing the transmembrane adaptor molecule LAT. Together, our findings reveal insights into the spatiotemporal organization of TCR signaling activities and their roles in T cell activation.
{"title":"Antigen affinity modulates ERK pulsing frequency during T cell activation","authors":"Vera-Marie E. Dunlock, Sergi Regot","doi":"10.1126/scisignal.adw3709","DOIUrl":"10.1126/scisignal.adw3709","url":null,"abstract":"<div >T cells achieve precise antigen discrimination by relying on the temporal stability of T cell receptor (TCR) interactions with antigens. Given that time is central to antigen discrimination, we used real-time, single-cell imaging in a controlled TCR-antigen system to characterize extracellular signal–regulated kinase (ERK) signaling dynamics as a function of antigen affinity to better understand the temporal patterns of signaling downstream of the TCR. We found that intermediate-affinity antigens elicited pulsatile ERK activity at different frequencies and that T cell activation correlated with the cumulative amount of ERK activity. Mechanistically, we found that the ERK pulsing frequency depended on the rate of activity of the Src family kinase LCK at the plasma membrane, whereas mitogen-activated protein kinase (MAPK) kinase (MEK) modulated the amplitude of ERK signaling. Moreover, we showed that ERK activity dynamics in T cells depended on members of two upstream MAP3K groups: mixed lineage kinases (MLKs) and RAFs, which played distinct roles promoting or sustaining the formation of upstream signaling condensates containing the transmembrane adaptor molecule LAT. Together, our findings reveal insights into the spatiotemporal organization of TCR signaling activities and their roles in T cell activation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 920","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958201","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 : 2026-01-13DOI: 10.1126/scisignal.adp4326
Kai J. Winterberg, Vanessa Schwentner, Feng Gu, Franziska Möckl, Gaoyang Li, Andreas Bauche, Stefanie Etzold, Anette Rosche, Mariella Weiß, Nikolaus Thuille, Fritz Förster, Lena Woelk, René Werner, Dejan Kovacevic, Boris Fehse, Roberta Kurelic, Mikolaj Nawrocki, Samuel Huber, Hans-Willi Mittrücker, Chris Meier, Christa E. Müller, Gottfried Baier, Bjørn S. Skålhegg, Xavier de Deken, Christian Wahl-Schott, Thomas Mair, Bente Siebels, Roger Cugota Canals, Francesca Odoardi, Dmitri Lodygin, Alexander Flügel, Viacheslav O. Nikolaev, Björn-Philipp Diercks, Andreas H. Guse
T cell activation critically depends on the calcium ion (Ca2+)–mobilizing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate), which induces the formation of Ca2+ microdomains that initiate global Ca2+ signals. NAADP is produced in immune synapses in T cells by dual NADPH oxidase 2 (DUOX2). Here, we investigated the mechanisms that stimulate DUOX2 activity in T cells. DUOX2 activity was enhanced by a modest increase in intracellular Ca2+ concentration, similar to that induced by Ca2+ microdomains that arise in resting T cells through different T cell receptor (TCR)–independent mechanisms. In addition, DUOX2 was activated in vitro by phosphorylation of threonine-789 mediated by PKA Cβ or PKCθ, and genetic deficiency of PKA Cβ2 or PKCθ decreased NAADP-dependent Ca2+ microdomain formation in T cells. PKA Cβ2 was activated downstream of adenosine A2A receptors, independently of the TCR. In contrast, PKCθ was activated by the tyrosine kinase LCK downstream of TCR stimulation. Inhibition of A2A receptors or PKCθ to prevent full DUOX2 activation decreased the production of the proinflammatory cytokine IL-17 by effector T cells. Thus, full stimulation of NAADP signaling that is critical for T cell activation requires integration of multiple TCR-independent and -dependent signals with different spatiotemporal characteristics by DUOX2, a fine-tuning mechanism that could be relevant for inflammation.
T细胞的激活主要依赖于钙离子（Ca2+）动员第二信使NAADP（烟酸腺嘌呤二核苷酸磷酸），它诱导Ca2+微域的形成，启动全局Ca2+信号。NAADP通过双NADPH氧化酶2 （DUOX2）在T细胞的免疫突触中产生。在这里，我们研究了刺激T细胞中DUOX2活性的机制。DUOX2活性通过细胞内Ca2+浓度的适度增加而增强，类似于通过不同的T细胞受体（TCR）独立机制在静息T细胞中产生的Ca2+微域诱导。此外，在体外，PKA Cβ或PKCθ介导的苏氨酸-789磷酸化激活了DUOX2， PKA Cβ2或PKCθ的遗传缺陷减少了T细胞中naadp依赖性Ca2+微结构域的形成。PKA c - β2在腺苷A2A受体下游被激活，独立于TCR。相反，PKCθ在TCR刺激的下游被酪氨酸激酶LCK激活。抑制A2A受体或PKCθ以防止DUOX2完全激活，可减少效应T细胞产生的促炎细胞因子IL-17。因此，充分刺激对T细胞活化至关重要的NAADP信号需要通过DUOX2整合具有不同时空特征的多个tcr独立和依赖信号，这是一种可能与炎症相关的微调机制。
{"title":"Multiple signaling events are required for NAADP synthesis by DUOX2 and formation of Ca2+ microdomains to initiate T cell activation","authors":"Kai J. Winterberg, Vanessa Schwentner, Feng Gu, Franziska Möckl, Gaoyang Li, Andreas Bauche, Stefanie Etzold, Anette Rosche, Mariella Weiß, Nikolaus Thuille, Fritz Förster, Lena Woelk, René Werner, Dejan Kovacevic, Boris Fehse, Roberta Kurelic, Mikolaj Nawrocki, Samuel Huber, Hans-Willi Mittrücker, Chris Meier, Christa E. Müller, Gottfried Baier, Bjørn S. Skålhegg, Xavier de Deken, Christian Wahl-Schott, Thomas Mair, Bente Siebels, Roger Cugota Canals, Francesca Odoardi, Dmitri Lodygin, Alexander Flügel, Viacheslav O. Nikolaev, Björn-Philipp Diercks, Andreas H. Guse","doi":"10.1126/scisignal.adp4326","DOIUrl":"10.1126/scisignal.adp4326","url":null,"abstract":"<div >T cell activation critically depends on the calcium ion (Ca<sup>2+</sup>)–mobilizing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate), which induces the formation of Ca<sup>2+</sup> microdomains that initiate global Ca<sup>2+</sup> signals. NAADP is produced in immune synapses in T cells by dual NADPH oxidase 2 (DUOX2). Here, we investigated the mechanisms that stimulate DUOX2 activity in T cells. DUOX2 activity was enhanced by a modest increase in intracellular Ca<sup>2+</sup> concentration, similar to that induced by Ca<sup>2+</sup> microdomains that arise in resting T cells through different T cell receptor (TCR)–independent mechanisms. In addition, DUOX2 was activated in vitro by phosphorylation of threonine-789 mediated by PKA Cβ or PKCθ, and genetic deficiency of PKA Cβ2 or PKCθ decreased NAADP-dependent Ca<sup>2+</sup> microdomain formation in T cells. PKA Cβ2 was activated downstream of adenosine A<sub>2A</sub> receptors, independently of the TCR. In contrast, PKCθ was activated by the tyrosine kinase LCK downstream of TCR stimulation. Inhibition of A<sub>2A</sub> receptors or PKCθ to prevent full DUOX2 activation decreased the production of the proinflammatory cytokine IL-17 by effector T cells. Thus, full stimulation of NAADP signaling that is critical for T cell activation requires integration of multiple TCR-independent and -dependent signals with different spatiotemporal characteristics by DUOX2, a fine-tuning mechanism that could be relevant for inflammation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 920","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958202","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 : 2026-01-06DOI: 10.1126/scisignal.adw1483
Mengru Gao, ShaoKun Zang, Yanqing Zhu, Kun Xi, Yage Du, Shizhuo Cheng, Luwei Miao, Yanhui Lu, Chunyou Mao, Yan Zhang, Xin Ma
Hydroxycarboxylic acid receptor 1 (HCAR1) is a class A G protein–coupled receptor (GPCR) that is activated by the endogenous metabolite l-lactate and that plays an important role in various metabolic and inflammatory disorders. HCAR1 uses distinct ligand recognition and self-activation mechanisms to mediate specific pathophysiological functions through Gαi/o and β-arrestin signaling pathways. To support effective drug development targeting HCAR1, we investigated ligand recognition and activation mechanisms through cryo–electron microscopy (cryo-EM) structures of the HCAR1-Gαi1 complex in the apo state or with l-lactate or with the synthetic agonist CHBA. Compared with other HCARs, HCAR1 has a more compact binding pocket, which is stabilized by three unique disulfide bonds. l-lactate exhibited a flexible binding mode and relatively weak intermolecular interactions, thus requiring millimolar concentrations for receptor activation. In contrast, the binding of CHBA was more stable because of its chlorinated benzene ring, thus resulting in improved agonist potency. Structural comparisons with HCAR2 identified critical residues that restrict the size of the binding pocket of HCAR1 and influence ligand selectivity. Self-activation of HCAR1 is driven by conformational rearrangements within extracellular loop 2, with Phe168ECL2 playing a pivotal role as the key agonist. Together, these results clarify the mechanisms underlying HCAR1 activation, self-activation, and ligand selectivity, providing a structural framework for the design of high-affinity, selective agonists and inverse agonists with minimized off-target effects.
{"title":"Structural insights into the activation mechanism of the human metabolite receptor HCAR1","authors":"Mengru Gao, ShaoKun Zang, Yanqing Zhu, Kun Xi, Yage Du, Shizhuo Cheng, Luwei Miao, Yanhui Lu, Chunyou Mao, Yan Zhang, Xin Ma","doi":"10.1126/scisignal.adw1483","DOIUrl":"10.1126/scisignal.adw1483","url":null,"abstract":"<div >Hydroxycarboxylic acid receptor 1 (HCAR1) is a class A G protein–coupled receptor (GPCR) that is activated by the endogenous metabolite <span>l</span>-lactate and that plays an important role in various metabolic and inflammatory disorders. HCAR1 uses distinct ligand recognition and self-activation mechanisms to mediate specific pathophysiological functions through Gα<sub>i/o</sub> and β-arrestin signaling pathways. To support effective drug development targeting HCAR1, we investigated ligand recognition and activation mechanisms through cryo–electron microscopy (cryo-EM) structures of the HCAR1-Gα<sub>i1</sub> complex in the apo state or with <span>l</span>-lactate or with the synthetic agonist CHBA. Compared with other HCARs, HCAR1 has a more compact binding pocket, which is stabilized by three unique disulfide bonds. <span>l</span>-lactate exhibited a flexible binding mode and relatively weak intermolecular interactions, thus requiring millimolar concentrations for receptor activation. In contrast, the binding of CHBA was more stable because of its chlorinated benzene ring, thus resulting in improved agonist potency. Structural comparisons with HCAR2 identified critical residues that restrict the size of the binding pocket of HCAR1 and influence ligand selectivity. Self-activation of HCAR1 is driven by conformational rearrangements within extracellular loop 2, with Phe168<sup>ECL2</sup> playing a pivotal role as the key agonist. Together, these results clarify the mechanisms underlying HCAR1 activation, self-activation, and ligand selectivity, providing a structural framework for the design of high-affinity, selective agonists and inverse agonists with minimized off-target effects.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"19 919","pages":""},"PeriodicalIF":6.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905282","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 : 2026-01-06DOI: 10.1126/scisignal.adx8300
Hyunbae Kim, Pattaraporn Thepsuwan, Juncheng Wei, Donghong Ju, Qi Chen, Xiaohong Zhang, Li Li, Jie Xu, Xin Tong, Shengyi Sun, Chuan He, Lei Yin, Deyu Fang, Kezhong Zhang
Hepatic lipid metabolism is regulated by circadian rhythms and dynamically responds to nutrient availability, such that lipid synthesis, oxidation, and storage are temporally coordinated. We demonstrated that the endoplasmic reticulum (ER)–localized E3 ubiquitin ligase HRD1 stimulated lipid accumulation in the liver by decreasing the N6-methyladenosine (m6A) methylation and expression of mRNAs encoding factors involved in lipid metabolism. In mouse livers, m6A RNA modification and the expression of mRNAs encoding the m6A writer METTL14 and the m6A reader YTHDF3 were under circadian control and inversely correlated with the abundance of HRD1. m6A RNA sequencing analyses revealed that HRD1 and the m6A writer METTL14 had opposing roles in the m6A modification and expression of mRNAs encoding factors involved in fatty acid metabolism. In vivo, hepatic lipid accumulation and triglyceride amounts were decreased in mice with hepatic HRD1 deficiency fed a high-fat diet but increased in mice with hepatic METTL14 or YTHDF deficiency fed normal chow. Mechanistically, HRD1 mediated the polyubiquitination and degradation of PPARα, which transcriptionally activated METTL14 and YTHDF3 expression in the liver. Our work identifies a pathway regulated by circadian rhythms or nutrients in which HRD1 promotes the degradation of PPARα to decrease the m6A modification and expression of hepatic mRNAs encoding factors involved in lipid metabolism.
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