Pub Date : 2024-10-29DOI: 10.1126/scisignal.adu1029
Amy E. Baek
A neuropeptide-receptor pair promotes the differentiation of TH1 cells and enhances their response to viral infection.
一对神经肽-受体促进了 TH1 细胞的分化，并增强了它们对病毒感染的反应。
{"title":"Neurons go antiviral","authors":"Amy E. Baek","doi":"10.1126/scisignal.adu1029","DOIUrl":"10.1126/scisignal.adu1029","url":null,"abstract":"<div >A neuropeptide-receptor pair promotes the differentiation of T<sub>H</sub>1 cells and enhances their response to viral infection.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 860","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541120","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 : 2024-10-29DOI: 10.1126/scisignal.adl5100
Vincent Rondeau, Maria Kalogeraki, Lilian Roland, Zeina Abou Nader, Vanessa Gourhand, Amélie Bonaud, Julia Lemos, Mélanie Khamyath, Clémentine Moulin, Bérénice Schell, Marc Delord, Ghislain Bidaut, Séverine Lecourt, Christelle Freitas, Adrienne Anginot, Nathalie Mazure, David H. McDermott, Véronique Parietti, Niclas Setterblad, Nicolas Dulphy, Françoise Bachelerie, Michel Aurrand-Lions, Daniel Stockholm, Camille Lobry, Philip M. Murphy, Marion Espéli, Stéphane J. C. Mancini, Karl Balabanian
Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated CXCR4 mutation (CXCR41013) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in CXCR41013 knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in CXCR41013 knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation.
{"title":"CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism","authors":"Vincent Rondeau, Maria Kalogeraki, Lilian Roland, Zeina Abou Nader, Vanessa Gourhand, Amélie Bonaud, Julia Lemos, Mélanie Khamyath, Clémentine Moulin, Bérénice Schell, Marc Delord, Ghislain Bidaut, Séverine Lecourt, Christelle Freitas, Adrienne Anginot, Nathalie Mazure, David H. McDermott, Véronique Parietti, Niclas Setterblad, Nicolas Dulphy, Françoise Bachelerie, Michel Aurrand-Lions, Daniel Stockholm, Camille Lobry, Philip M. Murphy, Marion Espéli, Stéphane J. C. Mancini, Karl Balabanian","doi":"10.1126/scisignal.adl5100","DOIUrl":"10.1126/scisignal.adl5100","url":null,"abstract":"<div >Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated <i>CXCR4</i> mutation (<i>CXCR4<sup>1013</sup></i>) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in <i>CXCR4<sup>1013</sup></i> knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in <i>CXCR4<sup>1013</sup></i> knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 860","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541122","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}
Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell–specific deficiency of Piezo1 (Ghrl-Piezo1−/−) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1−/− mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1−/− mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.
{"title":"Mechanosensing by Piezo1 in gastric ghrelin cells contributes to hepatic lipid homeostasis in mice","authors":"Jinshan Zhang, Yawen Zhao, Shaohong Wu, Mengxue Han, Luyang Gao, Ke Yang, Hui Chen, Cunchuan Wang, Geyang Xu","doi":"10.1126/scisignal.adq9463","DOIUrl":"10.1126/scisignal.adq9463","url":null,"abstract":"<div >Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell–specific deficiency of <i>Piezo1</i> (<i>Ghrl-Piezo1<sup>−/−</sup></i>) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in <i>Ghrl-Piezo1<sup>−/−</sup></i> mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in <i>Ghrl-Piezo1<sup>−/−</sup></i> mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 859","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adq9463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511662","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 : 2024-10-22DOI: 10.1126/scisignal.adi8753
Teresa Rosenlehner, Stefanie Pennavaria, Batuhan Akçabozan, Shiva Jahani, Thomas J. O''Neill, Daniel Krappmann, Tobias Straub, Jan Kranich, Reinhard Obst
Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.
核小体中的核糖体生物合成是一个耗能过程，由所有 RNA 聚合酶和数百种辅助蛋白质驱动。我们研究了活化的T淋巴细胞如何通过T细胞受体（TCR）信号和多蛋白复合物mTORC1和mTORC2（两者都含有激酶mTOR）来调节这一过程。缺失 mTORC1 会减缓 T 细胞的增殖，每次连续分裂都会进一步延迟，而缺失 mTORC2 则不会产生这种效应。mTORC1 信号受传统 TCR 信号成分的刺激，反之，抑制 mTORC1 则会降低 TCR 的敏感性。TCR激活所诱导的每个细胞RNA量的大幅增加因mTORC1的缺失而减少50%，但mTORC2或S6激酶1和2的缺失却没有减少，而S6激酶1和2是mTORC1的下游激活因子。RNA-seq数据显示，mTORC1的缺乏会降低所有RNA生物型的丰度，尽管在活化的T细胞中，rRNA的加工基本完好无损。使用新生前 rRNA 的 FISH 探针进行成像细胞测量显示，缺失 mTORC1（而非 mTORC2）会减少核极活性转录位点的数量并扩大其范围。因此，在缺乏 mTORC1 的情况下，蛋白质翻译减少了 50%。抑制 RNA 聚合酶 I 不仅会阻断细胞增殖，还会阻断 mTORC1 信号传导。我们的数据表明，TCR 信号、mTORC1 活性和核仁中的核糖体生物合成在克隆扩增 T 细胞的生物量产生过程中相互调节。
{"title":"Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells","authors":"Teresa Rosenlehner, Stefanie Pennavaria, Batuhan Akçabozan, Shiva Jahani, Thomas J. O''Neill, Daniel Krappmann, Tobias Straub, Jan Kranich, Reinhard Obst","doi":"10.1126/scisignal.adi8753","DOIUrl":"10.1126/scisignal.adi8753","url":null,"abstract":"<div >Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 859","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511664","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 : 2024-10-15DOI: 10.1126/scisignal.adn6324
Alba de Juan, Darawan Tabtim-On, Alice Coillard, Burkhard Becher, Christel Goudot, Elodie Segura
Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4–induced transcriptional responses and inhibited the IL-4–induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.
{"title":"The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters","authors":"Alba de Juan, Darawan Tabtim-On, Alice Coillard, Burkhard Becher, Christel Goudot, Elodie Segura","doi":"10.1126/scisignal.adn6324","DOIUrl":"10.1126/scisignal.adn6324","url":null,"abstract":"<div >Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4–induced transcriptional responses and inhibited the IL-4–induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 858","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439163","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 : 2024-10-15DOI: 10.1126/scisignal.adt7163
Leslie K. Ferrarelli
Too much or too little tau in glial cells enables the accumulation of neurotoxic oxidative stress.
神经胶质细胞中的 tau 含量过多或过少，都会导致神经毒性氧化应激的积累。
{"title":"The Goldilocks effect of glial tau","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.adt7163","DOIUrl":"10.1126/scisignal.adt7163","url":null,"abstract":"<div >Too much or too little tau in glial cells enables the accumulation of neurotoxic oxidative stress.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 858","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439162","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 : 2024-10-08DOI: 10.1126/scisignal.adn5805
Omer Abraham, Shifra Ben-Dor, Inna Goliand, Rebecca Haffner-Krausz, Sarah Phoebeluc Colaiuta, Andrew Kovalenko, Avraham Yaron
Mitophagy eliminates dysfunctional mitochondria, and defects in this cellular housekeeping mechanism are implicated in various age-related diseases. Here, we found that mitophagy suppression by the protein Siah3 promoted developmental axonal remodeling in mice. Siah3-deficient mice displayed increased peripheral sensory innervation. Cultured Siah3-deficient sensory neurons exhibited delays in both axonal degeneration and caspase-3 activation in response to withdrawal of nerve growth factor. Mechanistically, Siah3 was transcriptionally induced by the loss of trophic support and formed a complex with the cytosolic E3 ubiquitin ligase parkin, a core component of mitophagy, in transfected cells. Axons of Siah3-deficient neurons mounted profound mitophagy upon initiation of degeneration but not under basal conditions. Neurons lacking both Siah3 and parkin did not exhibit the delay in trophic deprivation–induced axonal degeneration or the induction of axonal mitophagy that was seen in Siah3-deficient neurons. Our findings reveal that mitophagy regulation acts as a gatekeeper of a physiological axon elimination program.
{"title":"Siah3 acts as a physiological mitophagy suppressor that facilitates axonal degeneration","authors":"Omer Abraham, Shifra Ben-Dor, Inna Goliand, Rebecca Haffner-Krausz, Sarah Phoebeluc Colaiuta, Andrew Kovalenko, Avraham Yaron","doi":"10.1126/scisignal.adn5805","DOIUrl":"10.1126/scisignal.adn5805","url":null,"abstract":"<div >Mitophagy eliminates dysfunctional mitochondria, and defects in this cellular housekeeping mechanism are implicated in various age-related diseases. Here, we found that mitophagy suppression by the protein Siah3 promoted developmental axonal remodeling in mice. Siah3-deficient mice displayed increased peripheral sensory innervation. Cultured Siah3-deficient sensory neurons exhibited delays in both axonal degeneration and caspase-3 activation in response to withdrawal of nerve growth factor. Mechanistically, Siah3 was transcriptionally induced by the loss of trophic support and formed a complex with the cytosolic E3 ubiquitin ligase parkin, a core component of mitophagy, in transfected cells. Axons of Siah3-deficient neurons mounted profound mitophagy upon initiation of degeneration but not under basal conditions. Neurons lacking both Siah3 and parkin did not exhibit the delay in trophic deprivation–induced axonal degeneration or the induction of axonal mitophagy that was seen in Siah3-deficient neurons. Our findings reveal that mitophagy regulation acts as a gatekeeper of a physiological axon elimination program.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 857","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394722","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 : 2024-10-08DOI: 10.1126/scisignal.adn4694
Alexandre Martins do Nascimento, Rauni Borges Marques, Allan Pradelli Roldão, Ana Maria Rodrigues, Rodrigo Mendes Eslava, Camila Squarzoni Dale, Eduardo Moraes Reis, Deborah Schechtman
The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain–containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.
{"title":"Exploring protein-protein interactions for the development of new analgesics","authors":"Alexandre Martins do Nascimento, Rauni Borges Marques, Allan Pradelli Roldão, Ana Maria Rodrigues, Rodrigo Mendes Eslava, Camila Squarzoni Dale, Eduardo Moraes Reis, Deborah Schechtman","doi":"10.1126/scisignal.adn4694","DOIUrl":"10.1126/scisignal.adn4694","url":null,"abstract":"<div >The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain–containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 857","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394720","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 : 2024-10-08DOI: 10.1126/scisignal.ads1228
Rina L. Davidson, David J. Simon
Developmental axon pruning is controlled by a careful balance of pro- and anti-apoptotic signals, which are activated in response to external cues to sculpt mature neuronal circuitry. In this issue of Science Signaling, Abraham et al. define a safeguard against apoptotic axon pruning and illustrate that Siah3 represses Parkin-mediated mitophagy to control the availability of axonal mitochondria that activate the pruning process.
{"title":"A Siah3 of relief: A role for mitophagy as a fail-safe during developmental axon pruning","authors":"Rina L. Davidson, David J. Simon","doi":"10.1126/scisignal.ads1228","DOIUrl":"10.1126/scisignal.ads1228","url":null,"abstract":"<div >Developmental axon pruning is controlled by a careful balance of pro- and anti-apoptotic signals, which are activated in response to external cues to sculpt mature neuronal circuitry. In this issue of <i>Science Signaling</i>, Abraham <i>et al.</i> define a safeguard against apoptotic axon pruning and illustrate that Siah3 represses Parkin-mediated mitophagy to control the availability of axonal mitochondria that activate the pruning process.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 857","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394719","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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