SORLA is a sorting receptor known to control the intracellular trafficking of the amyloid precursor protein, which impaired pathway has a central role in the development of Alzheimer’s disease (AD). Recently, genetic analyses confirmed the casual role for SORLA in AD, as coding variants and single nucleotide polymorphisms of SORL1 (gene encoding SORLA) were identified in individuals affected by early-onset AD and late-onset AD, respectively. However, many other different types of ligands were found to target the receptor, thus strongly indicating that SORLA can exert multifunctional activities. In the current review, we provide an overview of the multi-ligand properties of SORLA, showing how this complex receptor is involved in a variety of biological functions.
{"title":"20 Years Anniversary for SORLA/SORL1 (1996-2016)","authors":"G. Monti, O. Andersen","doi":"10.14800/rci.1611","DOIUrl":"https://doi.org/10.14800/rci.1611","url":null,"abstract":"SORLA is a sorting receptor known to control the intracellular trafficking of the amyloid precursor protein, which impaired pathway has a central role in the development of Alzheimer’s disease (AD). Recently, genetic analyses confirmed the casual role for SORLA in AD, as coding variants and single nucleotide polymorphisms of SORL1 (gene encoding SORLA) were identified in individuals affected by early-onset AD and late-onset AD, respectively. However, many other different types of ligands were found to target the receptor, thus strongly indicating that SORLA can exert multifunctional activities. In the current review, we provide an overview of the multi-ligand properties of SORLA, showing how this complex receptor is involved in a variety of biological functions.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81842265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leptin is identified as a mouse obesity gene, which is also preserved in humans. Leptin receptor is highly expressed in the hypothalamus relative to other tissues; therefore, the function of leptin is mainly attributed to hypothalamic control of food intake and body weight. Although the expression of leptin receptors is not limited to the hypothalamus but is also present in other regions of the central nervous system (CNS), such as the spinal cord, the functions of leptin and leptin receptor in the CNS have not been fully clarified. In this research highlight, we focus on the novel function of leptin in CNS remyelination in pathologic conditions, such as the demyelination mouse model. Because remyelination is a crucial process for repair of neuronal networks after injury and wound healing, knowledge of the underlying molecular mechanism of remyelination is useful to establish a therapeutic strategy against demyelinating diseases. We only revealed the role of leptin in remyelination at a histological level; however, a behavioral analysis and evidence of the beneficial effect of leptin for humans may add to knowledge of the effect of leptin on remyelination function.
{"title":"The role of leptin in the central nervous system remyelination","authors":"K. Matoba, R. Muramatsu, T. Yamashita","doi":"10.14800/RCI.1583","DOIUrl":"https://doi.org/10.14800/RCI.1583","url":null,"abstract":"Leptin is identified as a mouse obesity gene, which is also preserved in humans. Leptin receptor is highly expressed in the hypothalamus relative to other tissues; therefore, the function of leptin is mainly attributed to hypothalamic control of food intake and body weight. Although the expression of leptin receptors is not limited to the hypothalamus but is also present in other regions of the central nervous system (CNS), such as the spinal cord, the functions of leptin and leptin receptor in the CNS have not been fully clarified. In this research highlight, we focus on the novel function of leptin in CNS remyelination in pathologic conditions, such as the demyelination mouse model. Because remyelination is a crucial process for repair of neuronal networks after injury and wound healing, knowledge of the underlying molecular mechanism of remyelination is useful to establish a therapeutic strategy against demyelinating diseases. We only revealed the role of leptin in remyelination at a histological level; however, a behavioral analysis and evidence of the beneficial effect of leptin for humans may add to knowledge of the effect of leptin on remyelination function.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78756604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gq G protein-coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein-expressing (GFAP + ) glia is essential for neuron-glia interaction in the Central Nervous System (CNS). However, the exploration of the roles of Gq-GPCR signaling in peripheral GFAP + glia has just begun. Our recent study showed that GFAP + glia in the sympathetic ganglia, namely satellite glial cells (SGCs), positively modulate sympathetic-regulated cardiac functions following their Gq-GPCR activation. In this research highlight, we discuss the significance of satellite glial modulation of sympathetic nerve activity (SNA) in both physiology and in diseases. We also present a new experimental strategy for manipulating satellite glial signaling in the sympathetic ganglia using adeno-associated virus (AAV). The success of targeted viral transduction in ganglionic SGCs suggest a strong therapeutic potential of targeting sympathetic glia for the treatment of cardiovascular diseases (CVDs).
{"title":"Targeting sympathetic glia for treating cardiovascular diseases","authors":"A. Xie, Angelo Chaia, K. McCarthy","doi":"10.14800/RCI.1572","DOIUrl":"https://doi.org/10.14800/RCI.1572","url":null,"abstract":"Gq G protein-coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein-expressing (GFAP + ) glia is essential for neuron-glia interaction in the Central Nervous System (CNS). However, the exploration of the roles of Gq-GPCR signaling in peripheral GFAP + glia has just begun. Our recent study showed that GFAP + glia in the sympathetic ganglia, namely satellite glial cells (SGCs), positively modulate sympathetic-regulated cardiac functions following their Gq-GPCR activation. In this research highlight, we discuss the significance of satellite glial modulation of sympathetic nerve activity (SNA) in both physiology and in diseases. We also present a new experimental strategy for manipulating satellite glial signaling in the sympathetic ganglia using adeno-associated virus (AAV). The success of targeted viral transduction in ganglionic SGCs suggest a strong therapeutic potential of targeting sympathetic glia for the treatment of cardiovascular diseases (CVDs).","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89197445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Chavan, S. Bapat, V. Patil, A. Chowdhary, A. Kale
Influenza viruses are major human pathogens accountable for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need yearly updating and give limited protection. In addition, the currently available drugs suffer from the rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Recent advances in the understanding of Influenza virus replication have discovered a number of cellular drug targets that counteract viral drug resistance. With expanded bioinformatics’ knowledge on computational modeling and molecular dynamic stimulations, novel small molecule inhibitors of herbal/ayurvedic origin are being explored due to their non-toxicity and affordability. Using in-silico techniques the structural details and information of influenza protein have been studied to identify the potential drugs for inhibition. Further, we have discussed the various computational studies carried out on major protein/targets of Influenza which could provide new clues for a newer class of antiviral (ayurvedic) drugs. In the years to come ahead, the influenza treatment will go through major changes, with advancing our knowledge of pathogenesis as new methods becoming clinically validated.
{"title":"Computational analysis in Influenza virus","authors":"R. Chavan, S. Bapat, V. Patil, A. Chowdhary, A. Kale","doi":"10.14800/RCI.1574","DOIUrl":"https://doi.org/10.14800/RCI.1574","url":null,"abstract":"Influenza viruses are major human pathogens accountable for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need yearly updating and give limited protection. In addition, the currently available drugs suffer from the rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Recent advances in the understanding of Influenza virus replication have discovered a number of cellular drug targets that counteract viral drug resistance. With expanded bioinformatics’ knowledge on computational modeling and molecular dynamic stimulations, novel small molecule inhibitors of herbal/ayurvedic origin are being explored due to their non-toxicity and affordability. Using in-silico techniques the structural details and information of influenza protein have been studied to identify the potential drugs for inhibition. Further, we have discussed the various computational studies carried out on major protein/targets of Influenza which could provide new clues for a newer class of antiviral (ayurvedic) drugs. In the years to come ahead, the influenza treatment will go through major changes, with advancing our knowledge of pathogenesis as new methods becoming clinically validated.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78903083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Our previous studies have shown that transplantation of Hypoxia-inducible factor-1α (HIF-1α) gene modified neural stem cells (NSCs) reduced brain injury by improving the survival of NSCs and protecting the vascular system. HIF-1α plays pivotal roles during hypoxia, and its downstream pathways might be the primary mechanisms for the growth of NSCs. However, there are very few studies reported whether HIF-1α regulates NSCs migration. In this study, to test the hypothesis that HIF-1α modulates migration of NSCs after cerebral ischemia, we compared the injection of HIF-1α gene recombinant adenovirus, and control adenovirus in ischemia penumbra at 24 h after transient middle cerebral artery occlusion (tMCAO). BrdU labeled NSCs were transplanted in the lateral ventricle at the same time in both groups. The modified neurological severity score (NSS) was used to evaluate neurological deficits. Immunohistochemistry for HIF-1α, BrdU, Slit2 and Robo1 were performed. Comparing with vehicle group HIF-1α group showed better behavioral recovery on day 21 and 28. Expression of HIF-1α in HIF-1α group is higher than that in vehicle group. In HIF-1α group, more BrdU-positive cells were found than that in vehicle group. There are increased Slit2 in HIF-1α group. However, robo1, a receptor of Slits is decreased than that in vehicle group. Thus, we concluded that in cerebral ischemia rat model HIF-1α increased NSCs migration by inhibiting Slit2-Robo1 pathway, and improved the neurological behavior. In conclusion, our results indicate that HIF-1α may be a potential therapeutic target for ischemic stroke through promoting neuroregeneration.
{"title":"HIF-1α promotes NSCs migration by modulating Slit2-Robo1 signaling after cerebral ischemia","authors":"Hua Ye, Minrong Chen, Wan-fu Wu","doi":"10.14800/RCI.1549","DOIUrl":"https://doi.org/10.14800/RCI.1549","url":null,"abstract":"Our previous studies have shown that transplantation of Hypoxia-inducible factor-1α (HIF-1α) gene modified neural stem cells (NSCs) reduced brain injury by improving the survival of NSCs and protecting the vascular system. HIF-1α plays pivotal roles during hypoxia, and its downstream pathways might be the primary mechanisms for the growth of NSCs. However, there are very few studies reported whether HIF-1α regulates NSCs migration. In this study, to test the hypothesis that HIF-1α modulates migration of NSCs after cerebral ischemia, we compared the injection of HIF-1α gene recombinant adenovirus, and control adenovirus in ischemia penumbra at 24 h after transient middle cerebral artery occlusion (tMCAO). BrdU labeled NSCs were transplanted in the lateral ventricle at the same time in both groups. The modified neurological severity score (NSS) was used to evaluate neurological deficits. Immunohistochemistry for HIF-1α, BrdU, Slit2 and Robo1 were performed. Comparing with vehicle group HIF-1α group showed better behavioral recovery on day 21 and 28. Expression of HIF-1α in HIF-1α group is higher than that in vehicle group. In HIF-1α group, more BrdU-positive cells were found than that in vehicle group. There are increased Slit2 in HIF-1α group. However, robo1, a receptor of Slits is decreased than that in vehicle group. Thus, we concluded that in cerebral ischemia rat model HIF-1α increased NSCs migration by inhibiting Slit2-Robo1 pathway, and improved the neurological behavior. In conclusion, our results indicate that HIF-1α may be a potential therapeutic target for ischemic stroke through promoting neuroregeneration.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76290050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell culture technology is used to model structural and functional properties of human organs under normal and pathological conditions “in a dish”. The most obvious reason to culture human breast-derived cells is our fundamental desire to understand and ultimately treat breast cancer. Highly reproducible serum-free formulations for long-term propagation of normal human breast epithelial cells have existed for more than three decades and have served to complement the insight gained from a vast number of established breast cancer cell lines. The unspoken dichotomy in the experimental approach, however, has lied in the puzzling fact that normal-derived cells show a more myoepithelial expression profile, while breast cancer cells show more of a luminal profile making these difficult to compare experimentally. Moreover, normal estrogen receptor positive (ER+) luminal cells, thought to be equivalents to the most frequent form of human breast cancer, the ER+ subtype, completely fail to grow under standard culture conditions. One might choose to ignore this fact since breast homeostasis relies on a stem cell hierarchy and stem cells reside in the myoepithelial compartment which, if given the right conditions, can differentiate into ER+ luminal cells. The problem with this is that myoepithelial cells in culture, for unknown reasons, fail to behave like myoepithelial cells in vivo. This review summarizes some of the progress that has been made in the field with regard to the ER+ luminal breast epithelial lineage, especially within a human context, and its relevance to human breast cancer.
{"title":"Zero to one: normal derived human ER+ cells in culture-proliferating","authors":"B. M. Hopkinson","doi":"10.14800/RCI.1449","DOIUrl":"https://doi.org/10.14800/RCI.1449","url":null,"abstract":"Cell culture technology is used to model structural and functional properties of human organs under normal and pathological conditions “in a dish”. The most obvious reason to culture human breast-derived cells is our fundamental desire to understand and ultimately treat breast cancer. Highly reproducible serum-free formulations for long-term propagation of normal human breast epithelial cells have existed for more than three decades and have served to complement the insight gained from a vast number of established breast cancer cell lines. The unspoken dichotomy in the experimental approach, however, has lied in the puzzling fact that normal-derived cells show a more myoepithelial expression profile, while breast cancer cells show more of a luminal profile making these difficult to compare experimentally. Moreover, normal estrogen receptor positive (ER+) luminal cells, thought to be equivalents to the most frequent form of human breast cancer, the ER+ subtype, completely fail to grow under standard culture conditions. One might choose to ignore this fact since breast homeostasis relies on a stem cell hierarchy and stem cells reside in the myoepithelial compartment which, if given the right conditions, can differentiate into ER+ luminal cells. The problem with this is that myoepithelial cells in culture, for unknown reasons, fail to behave like myoepithelial cells in vivo. This review summarizes some of the progress that has been made in the field with regard to the ER+ luminal breast epithelial lineage, especially within a human context, and its relevance to human breast cancer.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78427811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The understanding of cell death mechanisms is crucial for the development and application of novel anti-cancer therapies to avoid or circumvent drug-resistance in refractory malignancies. Impairment of apoptotic cell death plays a major role in therapy resistance and relapse of acute lymphoblastic leukemia (ALL) patients. Therefore, efforts are being directed at new agents reactivating apoptosis or inducing alternative cell death pathways such as necroptosis, a regulated form of necrosis. In a recent study published in Science Translational Medicine we show that the IAP (inhibitor of apoptosis proteins) inhibitor birinapant potently induces cell death in patient-derived ALL cells in vitro and in vivo through a receptor-interacting protein kinase 1- (RIP1) dependent mechanism. To define the cell death modality induced downstream of RIP1, we used a multicolor lentiCRISPR approach that allows simultaneous knockout of multiple genes. We observed that apoptosis and necroptosis are induced simultaneously as the inhibition of both pathways is required to restore cell viability upon birinapant treatment. This induction of dual cell death makes birinapant and other IAP inhibitors interesting agents for the treatment of refractory or drug resistant malignancies.
{"title":"Activation of necroptosis to overcome drug resistance in leukemia","authors":"B. Bornhauser, J. Aguadé-Gorgorió","doi":"10.14800/RCI.1440","DOIUrl":"https://doi.org/10.14800/RCI.1440","url":null,"abstract":"The understanding of cell death mechanisms is crucial for the development and application of novel anti-cancer therapies to avoid or circumvent drug-resistance in refractory malignancies. Impairment of apoptotic cell death plays a major role in therapy resistance and relapse of acute lymphoblastic leukemia (ALL) patients. Therefore, efforts are being directed at new agents reactivating apoptosis or inducing alternative cell death pathways such as necroptosis, a regulated form of necrosis. In a recent study published in Science Translational Medicine we show that the IAP (inhibitor of apoptosis proteins) inhibitor birinapant potently induces cell death in patient-derived ALL cells in vitro and in vivo through a receptor-interacting protein kinase 1- (RIP1) dependent mechanism. To define the cell death modality induced downstream of RIP1, we used a multicolor lentiCRISPR approach that allows simultaneous knockout of multiple genes. We observed that apoptosis and necroptosis are induced simultaneously as the inhibition of both pathways is required to restore cell viability upon birinapant treatment. This induction of dual cell death makes birinapant and other IAP inhibitors interesting agents for the treatment of refractory or drug resistant malignancies.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81891414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Martel-Pelletier, G. Valverde-Franco, J. Pelletier
Ephrin ligands and their Eph receptors have been implicated in the control of extracellular matrix of some tissues. Although ephrin-B2 and its specific receptor EphB4 were found to be involved in postembryonic control of bone homeostasis, their roles were unclear in musculoskeletal growth and development as well as in osteoarthritis pathology. The role of this ephrin system in musculoskeletal growth and development was delineated in vivo using a cartilage-specific ephrin-B2 knockout mouse model. Its role in osteoarthritis in vivo was explored in mice using a bone-specific overexpression of EphB4 in which osteoarthritis was induced, and in vitro in human osteoarthritic subchondral bone osteoblasts and chondrocytes. In vivo , ephrin-B2 demonstrated to be essential for normal long bone growth and development and its absence in cartilage led to knee and hip osteoarthritis features in aged mice. In vitro data showed that the ephrin-B2-induced EphB4 receptor positively impacted the abnormal metabolism of both osteoarthritic subchondral bone osteoblasts and chondrocytes. The bone‑specific EphB4 overexpression in mice validated the in vitro data in that it had beneficial effects not only on the osteoarthritic subchondral bone but also on the cartilage and synovial membrane, and further substantiated the hypothesis that by prophylactically protecting the subchondral bone, the genesis of osteoarthritis could be, at least in part, inhibited. In the context of identifying new candidates targeting osteoarthritis progression, this ephrin system is extremely attractive as a potential novel therapeutic avenue, as therapies having a more global articular approach may prove to be the most successful to arrest or slow the progression of this disease.
{"title":"The ephrin-B2/EphB4 system is required in musculoskeletal development and protects the articulation during osteoarthritis: a research highlight","authors":"J. Martel-Pelletier, G. Valverde-Franco, J. Pelletier","doi":"10.14800/RCI.1426","DOIUrl":"https://doi.org/10.14800/RCI.1426","url":null,"abstract":"Ephrin ligands and their Eph receptors have been implicated in the control of extracellular matrix of some tissues. Although ephrin-B2 and its specific receptor EphB4 were found to be involved in postembryonic control of bone homeostasis, their roles were unclear in musculoskeletal growth and development as well as in osteoarthritis pathology. The role of this ephrin system in musculoskeletal growth and development was delineated in vivo using a cartilage-specific ephrin-B2 knockout mouse model. Its role in osteoarthritis in vivo was explored in mice using a bone-specific overexpression of EphB4 in which osteoarthritis was induced, and in vitro in human osteoarthritic subchondral bone osteoblasts and chondrocytes. In vivo , ephrin-B2 demonstrated to be essential for normal long bone growth and development and its absence in cartilage led to knee and hip osteoarthritis features in aged mice. In vitro data showed that the ephrin-B2-induced EphB4 receptor positively impacted the abnormal metabolism of both osteoarthritic subchondral bone osteoblasts and chondrocytes. The bone‑specific EphB4 overexpression in mice validated the in vitro data in that it had beneficial effects not only on the osteoarthritic subchondral bone but also on the cartilage and synovial membrane, and further substantiated the hypothesis that by prophylactically protecting the subchondral bone, the genesis of osteoarthritis could be, at least in part, inhibited. In the context of identifying new candidates targeting osteoarthritis progression, this ephrin system is extremely attractive as a potential novel therapeutic avenue, as therapies having a more global articular approach may prove to be the most successful to arrest or slow the progression of this disease.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86773020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Quorum sensing activation by signal peptide pheromones (SP) in Gram-positive bacteria depends on a membrane-associated histidine kinase receptor, which senses the signal and triggers the signaling cascade for various cell density-dependent activities. However, relatively little is known of peptide pheromone-receptor interactions in these bacteria, largely because of technical challenges in working with membrane-associated proteins in these bacteria. Recently, we have described a genetic approach and several analysis methods to studying membrane topology and structure-function interaction of a quorum sensing pheromone receptor ComD in a Gram-positive bacterium Streptococcus mutans . Using these methods, we confirm that the membrane-spanning domain of the ComD protein forms six transmembrane segments and three extracellular loops, loopA, loopB and loopC. By mutational analyses of these three extracellular loops, we demonstrate that both loopC and loopB are required for signal recognition and quorum sensing activation, while loopA plays little role in signal detection. In particular, a deletion or substitution mutation of four residues NVIP within loopC abolishes signal recognition for quorum sensing activation. Consistent with these findings, the loopC and loopB mutants are completely or partially defective in bacteriocin production. We conclude that both loopC and loopB are required to form the signal peptide receptor and the residues NVIP of loopC are essential for signal recognition and quorum sensing activation in S. mutans .
{"title":"Structural and functional insights into a quorum-sensing signal peptide receptor, the ComD histidine protein kinase of streptococcus mutans","authors":"Xiaolin Tian, Yung-Hua Li","doi":"10.14800/RCI.1424","DOIUrl":"https://doi.org/10.14800/RCI.1424","url":null,"abstract":"Quorum sensing activation by signal peptide pheromones (SP) in Gram-positive bacteria depends on a membrane-associated histidine kinase receptor, which senses the signal and triggers the signaling cascade for various cell density-dependent activities. However, relatively little is known of peptide pheromone-receptor interactions in these bacteria, largely because of technical challenges in working with membrane-associated proteins in these bacteria. Recently, we have described a genetic approach and several analysis methods to studying membrane topology and structure-function interaction of a quorum sensing pheromone receptor ComD in a Gram-positive bacterium Streptococcus mutans . Using these methods, we confirm that the membrane-spanning domain of the ComD protein forms six transmembrane segments and three extracellular loops, loopA, loopB and loopC. By mutational analyses of these three extracellular loops, we demonstrate that both loopC and loopB are required for signal recognition and quorum sensing activation, while loopA plays little role in signal detection. In particular, a deletion or substitution mutation of four residues NVIP within loopC abolishes signal recognition for quorum sensing activation. Consistent with these findings, the loopC and loopB mutants are completely or partially defective in bacteriocin production. We conclude that both loopC and loopB are required to form the signal peptide receptor and the residues NVIP of loopC are essential for signal recognition and quorum sensing activation in S. mutans .","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"67 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86657499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The paracaspase MALT1 functions as a bifunctional regulator of lymphocyte activation following the engagement of antigen receptors. First, MALT1 scaffolds the CARMA1-BCL10-MALT1 (CBM) signaling complex in charge of activating the NF-κB transcription factor. Second, MALT1 proteolytic activity governs NF-κB fine-tuning and the homeostasis of the immune system. MALT1 is also constitutively activated in the activated B-cell like (ABC) subset of diffuse large B-cell lymphoma (DLBCL), and the discovery that its chemical inhibition is toxic has opened new perspectives of treatment. Yet, the nature of MALT1 substrates continues to be elucidated. Herein, we review the recent identification of the linear ubiquitin assembly chain complex (LUBAC) element HOIL1 as a new substrate for MALT1 in lymphocytes and lymphoma. We discuss how this processing may affect NF-κB signaling and impact on lymphocyte homeostasis.
{"title":"HOIL1 cleavage by MALT1, the knives are out","authors":"Tiphaine Douanne, N. Bidère","doi":"10.14800/RCI.1410","DOIUrl":"https://doi.org/10.14800/RCI.1410","url":null,"abstract":"The paracaspase MALT1 functions as a bifunctional regulator of lymphocyte activation following the engagement of antigen receptors. First, MALT1 scaffolds the CARMA1-BCL10-MALT1 (CBM) signaling complex in charge of activating the NF-κB transcription factor. Second, MALT1 proteolytic activity governs NF-κB fine-tuning and the homeostasis of the immune system. MALT1 is also constitutively activated in the activated B-cell like (ABC) subset of diffuse large B-cell lymphoma (DLBCL), and the discovery that its chemical inhibition is toxic has opened new perspectives of treatment. Yet, the nature of MALT1 substrates continues to be elucidated. Herein, we review the recent identification of the linear ubiquitin assembly chain complex (LUBAC) element HOIL1 as a new substrate for MALT1 in lymphocytes and lymphoma. We discuss how this processing may affect NF-κB signaling and impact on lymphocyte homeostasis.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"91 1","pages":"1410-1410"},"PeriodicalIF":0.0,"publicationDate":"2016-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90931342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}