Pub Date : 2024-01-30DOI: 10.1126/scisignal.adg2622
Abigail G. Wolpe, Melissa A. Luse, Christopher Baryiames, Wyatt J. Schug, Jacob B. Wolpe, Scott R. Johnstone, Luke S. Dunaway, Zuzanna J. Juśkiewicz, Skylar A. Loeb, Henry R. Askew Page, Yen-Lin Chen, Vikram Sabapathy, Caitlin M. Pavelec, Brent Wakefield, Eugenia Cifuentes-Pagano, Mykhaylo V. Artamonov, Avril V. Somlyo, Adam C. Straub, Rahul Sharma, Frank Beier, Eugene J. Barrett, Norbert Leitinger, Patrick J. Pagano, Swapnil K. Sonkusare, Stefanie Redemann, Linda Columbus, Silvia Penuela, Brant E. Isakson
Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell–specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H2O2-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.
{"title":"Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress","authors":"Abigail G. Wolpe, Melissa A. Luse, Christopher Baryiames, Wyatt J. Schug, Jacob B. Wolpe, Scott R. Johnstone, Luke S. Dunaway, Zuzanna J. Juśkiewicz, Skylar A. Loeb, Henry R. Askew Page, Yen-Lin Chen, Vikram Sabapathy, Caitlin M. Pavelec, Brent Wakefield, Eugenia Cifuentes-Pagano, Mykhaylo V. Artamonov, Avril V. Somlyo, Adam C. Straub, Rahul Sharma, Frank Beier, Eugene J. Barrett, Norbert Leitinger, Patrick J. Pagano, Swapnil K. Sonkusare, Stefanie Redemann, Linda Columbus, Silvia Penuela, Brant E. Isakson","doi":"10.1126/scisignal.adg2622","DOIUrl":"10.1126/scisignal.adg2622","url":null,"abstract":"<div >Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell–specific deficiency in <i>Panx3</i> had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca<sup>2+</sup> handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. <i>Panx3</i> deficiency was associated with increased expression of the gene encoding the H<sub>2</sub>O<sub>2</sub>-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H<sub>2</sub>O<sub>2</sub>-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in <i>Nox4</i> expression and in blood pressure seen in mice with endothelial <i>Panx3</i> deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adg2622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643228","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 : 2024-01-30DOI: 10.1126/scisignal.ado2601
Amy E. Baek
The DNA double-strand break sensor MRE11 is necessary to liberate cGAS and enable its activation by dsDNA.
DNA 双链断裂传感器 MRE11 是释放 cGAS 并使其被 dsDNA 激活所必需的。
{"title":"Free cGAS","authors":"Amy E. Baek","doi":"10.1126/scisignal.ado2601","DOIUrl":"10.1126/scisignal.ado2601","url":null,"abstract":"<div >The DNA double-strand break sensor MRE11 is necessary to liberate cGAS and enable its activation by dsDNA.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643227","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 : 2024-01-30DOI: 10.1126/scisignal.adi7861
Hema Kalyanaraman, Darren E. Casteel, Shyamsundar Pal China, Shunhui Zhuang, Gerry R. Boss, Renate B. Pilz
Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane–associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane–associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser515 by ERK increased the nuclear accumulation and binding of AR to the promoter of Ctnnb1, which encodes the transcription factor β-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of Ctnnb1 and CTNN1B, respectively, as well as β-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because β-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer.
{"title":"A plasma membrane–associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells","authors":"Hema Kalyanaraman, Darren E. Casteel, Shyamsundar Pal China, Shunhui Zhuang, Gerry R. Boss, Renate B. Pilz","doi":"10.1126/scisignal.adi7861","DOIUrl":"10.1126/scisignal.adi7861","url":null,"abstract":"<div >Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane–associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane–associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser<sup>515</sup> by ERK increased the nuclear accumulation and binding of AR to the promoter of <i>Ctnnb1</i>, which encodes the transcription factor β-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of <i>Ctnnb1</i> and <i>CTNN1B</i>, respectively, as well as β-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because β-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643226","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 : 2024-01-23DOI: 10.1126/scisignal.abo0465
Yingying Wang, Huili Yao, Yu Zhang, Ning Mu, Tong Lu, Zhiyuan Du, Yingdi Wu, Xiaopeng Li, Min Su, Ming Shao, Xiaoyang Sun, Ling Su, Xiangguo Liu
Primary cilia are enriched in signaling receptors, and defects in their formation or function can induce conditions such as polycystic kidney disease, postaxial hexadactyly, and microphthalmia. Mammalian Hedgehog (Hh) signaling is important in the development of primary cilia, and TMEM216, a transmembrane protein that localizes to the base of cilia, is also implicated in ciliogenesis in zebrafish. Here, we found that Tmem216-deficient mice had impaired Hh signaling and displayed typical ciliopathic phenotypes. These phenomena were also observed in cells deficient in TMEM216. Furthermore, TMEM216 interacted with core Hh signaling proteins, including SUFU, a negative regulator of Hh, and GLI2/GLI3, transcription factors downstream of Hh. The competition between TMEM216 and SUFU for binding to GLI2/GLI3 inhibited the cleavage of GLI2/GLI3 into their repressor forms, which resulted in the nuclear accumulation of full-length GLI2 and the decreased nuclear localization of cleaved GLI3, ultimately leading to the activation of Hh signaling. Together, these data suggest that the TMEM216-SUFU-GLI2/GLI3 axis plays a role in TMEM216 deficiency–induced ciliopathies and Hh signaling abnormalities.
{"title":"TMEM216 promotes primary ciliogenesis and Hedgehog signaling through the SUFU-GLI2/GLI3 axis","authors":"Yingying Wang, Huili Yao, Yu Zhang, Ning Mu, Tong Lu, Zhiyuan Du, Yingdi Wu, Xiaopeng Li, Min Su, Ming Shao, Xiaoyang Sun, Ling Su, Xiangguo Liu","doi":"10.1126/scisignal.abo0465","DOIUrl":"10.1126/scisignal.abo0465","url":null,"abstract":"<div >Primary cilia are enriched in signaling receptors, and defects in their formation or function can induce conditions such as polycystic kidney disease, postaxial hexadactyly, and microphthalmia. Mammalian Hedgehog (Hh) signaling is important in the development of primary cilia, and TMEM216, a transmembrane protein that localizes to the base of cilia, is also implicated in ciliogenesis in zebrafish. Here, we found that <i>Tmem216</i>-deficient mice had impaired Hh signaling and displayed typical ciliopathic phenotypes. These phenomena were also observed in cells deficient in TMEM216. Furthermore, TMEM216 interacted with core Hh signaling proteins, including SUFU, a negative regulator of Hh, and GLI2/GLI3, transcription factors downstream of Hh. The competition between TMEM216 and SUFU for binding to GLI2/GLI3 inhibited the cleavage of GLI2/GLI3 into their repressor forms, which resulted in the nuclear accumulation of full-length GLI2 and the decreased nuclear localization of cleaved GLI3, ultimately leading to the activation of Hh signaling. Together, these data suggest that the TMEM216-SUFU-GLI2/GLI3 axis plays a role in TMEM216 deficiency–induced ciliopathies and Hh signaling abnormalities.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543283","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 : 2024-01-23DOI: 10.1126/scisignal.ado0928
Leslie K. Ferrarelli
YTHDC1 activates the DNA repair kinase ATR to suppress bleomycin-induced lung fibrosis.
YTHDC1激活DNA修复激酶ATR，抑制博莱霉素诱导的肺纤维化
{"title":"Promoting DNA repair to prevent fibrosis","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.ado0928","DOIUrl":"10.1126/scisignal.ado0928","url":null,"abstract":"<div >YTHDC1 activates the DNA repair kinase ATR to suppress bleomycin-induced lung fibrosis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543275","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 : 2024-01-23DOI: 10.1126/scisignal.abg8145
Jared R. Coombs, Alina Zamoshnikova, Caroline L. Holley, Madhavi P. Maddugoda, Daniel Eng Thiam Teo, Camille Chauvin, Lionel F Poulin, Nazarii Vitak, Connie M. Ross, Manasa Mellacheruvu, Rebecca C. Coll, Leonhard X. Heinz, Sabrina S. Burgener, Stefan Emming, Mathias Chamaillard, Dave Boucher, Kate Schroder
Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens and immune pathology in autoinflammatory diseases. Inflammasomes assemble when an inflammasome scaffold protein senses an activating signal and forms a signaling platform with the inflammasome adaptor protein ASC. The NLRP subfamily of NOD-like receptors (NLRs) includes inflammasome nucleators (such as NLRP3) and also NLRP12, which is genetically linked to familial autoinflammatory disorders that resemble diseases caused by gain-of-function NLRP3 mutants that generate a hyperactive NLRP3 inflammasome. We performed a screen to identify ASC inflammasome–nucleating proteins among NLRs that have the canonical pyrin-NACHT-LRR domain structure. Only NLRP3 and NLRP6 could initiate ASC polymerization to form “specks,” and NLRP12 failed to nucleate ASC polymerization. However, wild-type NLRP12 inhibited ASC inflammasome assembly induced by wild-type and gain-of-function mutant NLRP3, an effect not seen with disease-associated NLRP12 mutants. The capacity of NLRP12 to suppress NLRP3 inflammasome assembly was limited to human NLRP3 and was not observed for wild-type murine NLRP3. Furthermore, peripheral blood mononuclear cells from patients with an NLRP12 mutant–associated inflammatory disorder produced increased amounts of the inflammatory cytokine IL-1β in response to NLRP3 stimulation. Thus, our findings provide insights into NLRP12 biology and suggest that NLRP3 inhibitors in clinical trials for NLRP3-driven diseases may also be effective in treating NLRP12-associated autoinflammatory diseases.
{"title":"NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome","authors":"Jared R. Coombs, Alina Zamoshnikova, Caroline L. Holley, Madhavi P. Maddugoda, Daniel Eng Thiam Teo, Camille Chauvin, Lionel F Poulin, Nazarii Vitak, Connie M. Ross, Manasa Mellacheruvu, Rebecca C. Coll, Leonhard X. Heinz, Sabrina S. Burgener, Stefan Emming, Mathias Chamaillard, Dave Boucher, Kate Schroder","doi":"10.1126/scisignal.abg8145","DOIUrl":"10.1126/scisignal.abg8145","url":null,"abstract":"<div >Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens and immune pathology in autoinflammatory diseases. Inflammasomes assemble when an inflammasome scaffold protein senses an activating signal and forms a signaling platform with the inflammasome adaptor protein ASC. The NLRP subfamily of NOD-like receptors (NLRs) includes inflammasome nucleators (such as NLRP3) and also NLRP12, which is genetically linked to familial autoinflammatory disorders that resemble diseases caused by gain-of-function NLRP3 mutants that generate a hyperactive NLRP3 inflammasome. We performed a screen to identify ASC inflammasome–nucleating proteins among NLRs that have the canonical pyrin-NACHT-LRR domain structure. Only NLRP3 and NLRP6 could initiate ASC polymerization to form “specks,” and NLRP12 failed to nucleate ASC polymerization. However, wild-type NLRP12 inhibited ASC inflammasome assembly induced by wild-type and gain-of-function mutant NLRP3, an effect not seen with disease-associated NLRP12 mutants. The capacity of NLRP12 to suppress NLRP3 inflammasome assembly was limited to human NLRP3 and was not observed for wild-type murine NLRP3. Furthermore, peripheral blood mononuclear cells from patients with an NLRP12 mutant–associated inflammatory disorder produced increased amounts of the inflammatory cytokine IL-1β in response to NLRP3 stimulation. Thus, our findings provide insights into NLRP12 biology and suggest that NLRP3 inhibitors in clinical trials for NLRP3-driven diseases may also be effective in treating NLRP12-associated autoinflammatory diseases.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543271","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 : 2024-01-16DOI: 10.1126/scisignal.abn1101
Tatiana Goncharov, László G. Kőműves, Matthias Kist, Erick R. Castellanos, Axel Witt, Anna V. Fedorova, Anita Izrael-Tomasevic, Kebing Yu, Mary Keir, Marissa L. Matsumoto, Domagoj Vucic
Ubiquitination is a posttranslational modification that is crucial for the dynamic regulation of diverse signaling pathways. To enhance our understanding of ubiquitination-mediated signaling, we generated a new class of bispecific antibodies that combine recognition of ubiquitination substrates and specific polyubiquitin linkages. RIP1-K63 and RIP1–linear (Lin) linkage polyubiquitin bispecific antibodies detected linkage-specific ubiquitination of the proinflammatory kinase RIP1 in cells and in tissues and revealed RIP1 ubiquitination by immunofluorescence. Similarly, ubiquitination of the RIP1-related kinase RIP2 with K63 or linear linkages was specifically detected with the RIP2-K63 and RIP2-Lin bispecific antibodies, respectively. Furthermore, using the RIP2-K63 and RIP2-Lin bispecific antibodies, we found prominent K63-linked and linear RIP2 ubiquitination in samples from patients with ulcerative colitis and Crohn’s disease. We also developed a bispecific antibody (K63-Lin) that simultaneously recognizes K63-linked and linear ubiquitination of components of various signaling pathways. Together, these bispecific antibodies represent a new class of reagents with the potential to be developed for the detection of inflammatory biomarkers.
{"title":"Simultaneous substrate and ubiquitin modification recognition by bispecific antibodies enables detection of ubiquitinated RIP1 and RIP2","authors":"Tatiana Goncharov, László G. Kőműves, Matthias Kist, Erick R. Castellanos, Axel Witt, Anna V. Fedorova, Anita Izrael-Tomasevic, Kebing Yu, Mary Keir, Marissa L. Matsumoto, Domagoj Vucic","doi":"10.1126/scisignal.abn1101","DOIUrl":"10.1126/scisignal.abn1101","url":null,"abstract":"<div >Ubiquitination is a posttranslational modification that is crucial for the dynamic regulation of diverse signaling pathways. To enhance our understanding of ubiquitination-mediated signaling, we generated a new class of bispecific antibodies that combine recognition of ubiquitination substrates and specific polyubiquitin linkages. RIP1-K63 and RIP1–linear (Lin) linkage polyubiquitin bispecific antibodies detected linkage-specific ubiquitination of the proinflammatory kinase RIP1 in cells and in tissues and revealed RIP1 ubiquitination by immunofluorescence. Similarly, ubiquitination of the RIP1-related kinase RIP2 with K63 or linear linkages was specifically detected with the RIP2-K63 and RIP2-Lin bispecific antibodies, respectively. Furthermore, using the RIP2-K63 and RIP2-Lin bispecific antibodies, we found prominent K63-linked and linear RIP2 ubiquitination in samples from patients with ulcerative colitis and Crohn’s disease. We also developed a bispecific antibody (K63-Lin) that simultaneously recognizes K63-linked and linear ubiquitination of components of various signaling pathways. Together, these bispecific antibodies represent a new class of reagents with the potential to be developed for the detection of inflammatory biomarkers.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.abn1101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479426","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 : 2024-01-16DOI: 10.1126/scisignal.adh7673
Oday Abushalbaq, Jiyeon Baek, Avraham Yaron, Tracy S. Tran
The precise development of neuronal morphologies is crucial to the establishment of synaptic circuits and, ultimately, proper brain function. Signaling by the axon guidance cue semaphorin 3A (Sema3A) and its receptor complex of neuropilin-1 and plexin-A4 has multifunctional outcomes in neuronal morphogenesis. Downstream activation of the RhoGEF FARP2 through interaction with the lysine-arginine-lysine motif of plexin-A4 and consequent activation of the small GTPase Rac1 promotes dendrite arborization, but this pathway is dispensable for axon repulsion. Here, we investigated the interplay of small GTPase signaling mechanisms underlying Sema3A-mediated dendritic elaboration in mouse layer V cortical neurons in vitro and in vivo. Sema3A promoted the binding of the small GTPase Rnd1 to the amino acid motif lysine-valine-serine (LVS) in the cytoplasmic domain of plexin-A4. Rnd1 inhibited the activity of the small GTPase RhoA and the kinase ROCK, thus supporting the activity of the GTPase Rac1, which permitted the growth and branching of dendrites. Overexpression of a dominant-negative RhoA, a constitutively active Rac1, or the pharmacological inhibition of ROCK activity rescued defects in dendritic elaboration in neurons expressing a plexin-A4 mutant lacking the LVS motif. Our findings provide insights into the previously unappreciated balancing act between Rho and Rac signaling downstream of specific motifs in plexin-A4 to mediate Sema3A-dependent dendritic elaboration in mammalian cortical neuron development.
{"title":"Balancing act of small GTPases downstream of plexin-A4 signaling motifs promotes dendrite elaboration in mammalian cortical neurons","authors":"Oday Abushalbaq, Jiyeon Baek, Avraham Yaron, Tracy S. Tran","doi":"10.1126/scisignal.adh7673","DOIUrl":"10.1126/scisignal.adh7673","url":null,"abstract":"<div >The precise development of neuronal morphologies is crucial to the establishment of synaptic circuits and, ultimately, proper brain function. Signaling by the axon guidance cue semaphorin 3A (Sema3A) and its receptor complex of neuropilin-1 and plexin-A4 has multifunctional outcomes in neuronal morphogenesis. Downstream activation of the RhoGEF FARP2 through interaction with the lysine-arginine-lysine motif of plexin-A4 and consequent activation of the small GTPase Rac1 promotes dendrite arborization, but this pathway is dispensable for axon repulsion. Here, we investigated the interplay of small GTPase signaling mechanisms underlying Sema3A-mediated dendritic elaboration in mouse layer V cortical neurons in vitro and in vivo. Sema3A promoted the binding of the small GTPase Rnd1 to the amino acid motif lysine-valine-serine (LVS) in the cytoplasmic domain of plexin-A4. Rnd1 inhibited the activity of the small GTPase RhoA and the kinase ROCK, thus supporting the activity of the GTPase Rac1, which permitted the growth and branching of dendrites. Overexpression of a dominant-negative RhoA, a constitutively active Rac1, or the pharmacological inhibition of ROCK activity rescued defects in dendritic elaboration in neurons expressing a plexin-A4 mutant lacking the LVS motif. Our findings provide insights into the previously unappreciated balancing act between Rho and Rac signaling downstream of specific motifs in plexin-A4 to mediate Sema3A-dependent dendritic elaboration in mammalian cortical neuron development.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479424","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 : 2024-01-16DOI: 10.1126/scisignal.adn9627
John F. Foley
The actions of glucagon-like peptide 1 receptor agonists in the CNS reduce systemic inflammation.
胰高血糖素样肽 1 受体激动剂在中枢神经系统中的作用可减轻全身炎症。
{"title":"Systemic inflammation from the brain","authors":"John F. Foley","doi":"10.1126/scisignal.adn9627","DOIUrl":"10.1126/scisignal.adn9627","url":null,"abstract":"<div >The actions of glucagon-like peptide 1 receptor agonists in the CNS reduce systemic inflammation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479427","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 : 2024-01-09DOI: 10.1126/scisignal.adh1641
Tapas Mukherjee, Naveen Kumar, Meenakshi Chawla, Dana J. Philpott, Soumen Basak
Inflammatory bowel disease (IBD) is an idiopathic, chronic condition characterized by episodes of inflammation in the gastrointestinal tract. The nuclear factor κB (NF-κB) system describes a family of dimeric transcription factors. Canonical NF-κB signaling is stimulated by and enhances inflammation, whereas noncanonical NF-κB signaling contributes to immune organogenesis. Dysregulation of NF-κB factors drives various inflammatory pathologies, including IBD. Signals from many immune sensors activate NF-κB subunits in the intestine, which maintain an equilibrium between local microbiota and host responses. Genetic association studies of patients with IBD and preclinical mouse models confirm the importance of the NF-κB system in host defense in the gut. Other studies have investigated the roles of these factors in intestinal barrier function and in inflammatory gut pathologies associated with IBD. NF-κB signaling modulates innate and adaptive immune responses and the production of immunoregulatory proteins, anti-inflammatory cytokines, antimicrobial peptides, and other tolerogenic factors in the intestine. Furthermore, genetic studies have revealed critical cell type–specific roles for NF-κB proteins in intestinal immune homeostasis, inflammation, and restitution that contribute to the etiopathology of IBD-associated manifestations. Here, we summarize our knowledge of the roles of these NF-κB pathways, which are activated in different intestinal cell types by specific ligands, and their cross-talk, in fueling aberrant intestinal inflammation. We argue that an in-depth understanding of aberrant immune signaling mechanisms may hold the key to identifying predictive or prognostic biomarkers and developing better therapeutics against inflammatory gut pathologies.
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