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Francois Casas - One of the best experts on this subject based on the ideXlab platform.
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exacerbated age related hearing loss in mice lacking the P43 mitochondrial t3 receptor
BMC Biology, 2021Co-Authors: Francois Casas, Corentin Affortit, Sabine Ladrech, J C Ceccato, Jerome Bourien, Carolanne CoyatAbstract:Age-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of P43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in P43−/− mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology. We found that the P43−/− mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in P43−/− mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, P43−/− mice were also more vulnerable to noise-induced hearing loss. These results demonstrate for the first time a requirement for P43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.
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Regulation of mitochondrial activity controls the duration of skeletal muscle regeneration in response to injury
Scientific Reports, 2019Co-Authors: L. Pessemesse, Chantal Cabello, Gerard Cabello, Fabienne Cortade, Emilie Blanchet, Lionel Tintignac, Elodie Jublanc, Rémi Demangel, Chamroeun Sar, Francois CasasAbstract:Thyroid hormone is a major regulator of skeletal muscle development and repair, and also a key regulator of mitochondrial activity. We have previously identified a 43 kDa truncated form of the nuclear T3 receptor TR alpha 1 (P43) which stimulates mitochondrial activity and regulates skeletal muscle features. However, its role in skeletal muscle regeneration remains to be addressed. To this end, we performed acute muscle injury induced by cardiotoxin in mouse tibialis in two mouse models where P43 is overexpressed in or depleted from skeletal muscle. The measurement of muscle fiber size distribution at different time point (up to 70 days) upon injury lead us to unravel requirement of the P43 signaling pathway for satellite cells dependent muscle regeneration; strongly delayed in the absence of P43; whereas the overexpression of the receptor enhances of the regeneration process. In addition, we found that satellite cells derived from P43-Tg mice display higher proliferation rates when cultured in vitro when compared to control myoblasts, whereas P43-/- satellites shows reduced proliferation capacity. These finding strongly support that P43 plays an important role in vivo by controling the duration of skeletal muscle regeneration after acute injury, possibly through the regulation of mitochondrial activity and myoblasts proliferation.
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Skeletal muscle expression of P43, a truncated thyroid hormone receptor α, affects lipid composition and metabolism
Journal of Bioenergetics and Biomembranes, 2018Co-Authors: Francois Casas, L. Pessemesse, Christine Coudray, Gilles Fouret, Jérôme Lecomte, Fabienne Cortade, Emilie Blanchet, Chantal Wrutniak Cabello, Christine Feillet CoudrayAbstract:Thyroid hormone is a major regulator of metabolism and mitochondrial function. Thyroid hormone also affects reactions in almost all pathways of lipids metabolism and as such is considered as the main hormonal regulator of lipid biogenesis. The aim of this study was to explore the possible involvement of P43, a 43 Kda truncat ed form of the nuclear thyroid hormone receptor TR α1 which stimulates mitochondrial activity. Therefore, using mouse models overexpressing P43 in skeletal muscle (P43-Tg) or lacking P43 (P43−/−), we have investigated the lipid composition in quadriceps muscle and in mitochondria. Here, we reported in the quadriceps muscle of P43 −/−mice, a fall in triglycerides, an inhibition of monounsaturated fatty acids (MUFA) synthesis, an increase in elongase index and andecrease in desaturase index. However, in mitochondria from P43−/−mice, fatty acid profile was barely modified. In the quadriceps muscle of P43-Tg mice, MUFA content was decreased whereas the unsaturation index was increased. In addition, in quadriceps mitochondria of P43-Tg mice, we found an increase of linoleic acid level and unsaturation index. Last, we showed that cardiolipin content, a key phospholipid for mitochondrial function, remained unchanged both in quadriceps muscle and in its mitochondria whatever the mice genotype. In conclusion, this study shows that muscle lipid content and fatty acid profile are strongly affected in skeletal muscle by P43 levels. We also demonstrate that regulation of cardiolipin biosynthesis by the thyroid hormone does not imply P43.
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thyroid hormone action the P43 mitochondrial pathway
Methods of Molecular Biology, 2018Co-Authors: Chantal Wrutniakcabello, Francois Casas, Gerard CabelloAbstract:The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial pathway is now well established. The demonstration that TRα1 mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into mitochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones.The use of a T3 photo affinity label derivative (T3-PAL) allowed detecting two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRα1, mitochondrial T3 receptors were identified as truncated TRα1 forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that P43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. In vitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, and transformation. Generation of transgenic mice demonstrated the involvement of this mitochondrial pathway in the determination of muscle phenotype, glucose metabolism, and thermogenesis.
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Thyroid hormone action: The P43 mitochondrial pathway. Methods
2018Co-Authors: Chantal Wrutniak Cabello, Francois Casas, Gerard CabelloAbstract:The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial _pathway is now well established. The demonstration that TR.al mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into ttùtochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones. The use of a T3 photo affinity label derivative (T3-PAL) allowed detectiug two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRal, mitochondrial T3 receptors were identified as truncated T.Ral forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that P43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. In vitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, and transformation. Generation of transgenic mice demonstrated the involve1nent of this mitochondrial pathway in the determination of muscle phenotype, glucose metabolism, and thermogenesis.
Sunghoon Kim - One of the best experts on this subject based on the ideXlab platform.
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multi enzyme aminoacyl trna synthetase complex component aimp1 P43 as an important th1 mediator irc7p 428
Journal of Immunology, 2015Co-Authors: Dan Liang, Sunghoon Kim, Matthew M Halpert, Vanaja Konduri, Yunyu Chen, Doyeun Kim, Jonathan M Levitt, William K DeckerAbstract:Of professional antigen presenting cells, only the dendritic cells (DC) are regarded as initiators of adaptive immune responses. Previously we identified a Th1 polarizing phenotype from DCs loaded with overlapping (homologous) MHC class I and II determinants, including augmented DC IL-12 production, generation of CD8 + cytolytic effectors, and T cell IFNγ secretion, suggesting DC intrinsic mechanisms to recognize and compare antigenic epitopes. AIMp1/P43 is a structural component of the multi-enzyme aminoacyl-tRNA synthetase complex (mARS) and indicated by previous studies to be a pro-inflammatory cytokine. We identified high levels of P43 release correlated with degree of homology between antigenic epitopes on DC class I and II molecules. In vitro studies confirmed P43 deficiency impairs DC costimulatory and Th1 polarizing functions. It also reversely regulates the production of IFNγ and IL4 within T cells. In vivo, P43 deficiency abolishes the ability of DC to mediate effective response against B16 melanoma tumors, and leads to higher susceptibility to influenza viral infections. These data support our hypothesis that P43 is a critical Th1 polarizing effector molecule. We will investigate further into P43 functions in DC and T cell crosstalk, targeting candidate cell surface receptors and intracellular signaling pathways. Additionally, we will better characterize in vivo roles of P43 in anti-tumor and anti-viral models and seek to apply it as a novel vaccination adjuvant.
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degradation of aimp1 P43 induced by hepatitis c virus e2 leads to upregulation of tgf β signaling and increase in surface expression of gp96
PLOS ONE, 2014Co-Authors: Min Soo Kim, Sunghoon Kim, Heejoon MyungAbstract:Hepatitis C virus (HCV) causes chronic hepatitis leading to liver fibrosis and autoimmune diseases. AIMP1/P43 is a multifunctional protein initially known as a cofactor of aminoacyl tRNA synthetase complex. Its function includes negative regulation of TGF-β signaling and suppression of Lupus-like autoimmune disease by inhibition of surface expression of gp96. HCV E2 was shown to directly interact with AIMP1/P43 by GST pulldown assay and coimmunoprecipitation. Their subcellular colocalization was observed in an immunofluorescence confocal microscopy. We showed that HCV E2 led to degradation of AIMP1/P43 in two ways. First, in the presence of HCV E2, endogenous AIMP1/P43 was shown to be degraded in an ubiquitin-dependent proteasome pathway. Second, grp78, an ER chaperone, was shown to interact with and stabilize AIMP1/P43. And HCV E2 inhibited this interaction leading to reduction of cellular AIMP1/P43. The degradation of AIMP1/P43 by HCV E2 resulted in increase of TGF-β signaling and cell surface expression of gp96. Thus we suggest that these are novel mechanisms responsible for liver fibrosis and autoimmune diseases caused by HCV.
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msc P43 required for axonal development in motor neurons
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Xiaodong Zhu, Sunghoon Kim, Yang Liu, Yanqing Yin, Aiyun Shao, Bo Zhang, Jiawei ZhouAbstract:Neuron connectivity and correct neural function largely depend on axonal integrity. Neurofilaments (NFs) constitute the main cytoskeletal network maintaining the structural integrity of neurons and exhibit dynamic changes during axonal and dendritic growth. However, the mechanisms underlying axonal development and maintenance remain poorly understood. Here, we identify that multisynthetase complex P43 (MSC P43) is essential for NF assembly and axon maintenance. The MSC P43 protein was predominantly expressed in central neurons and interacted with NF light subunit in vivo. Mice lacking MSC P43 exhibited axon degeneration in motor neurons, defective neuromuscular junctions, muscular atrophy, and motor dysfunction. Furthermore, MSC P43 depletion in mice caused disorganization of the axonal NF network. Mechanistically, MSC P43 is required for maintaining normal phosphorylation levels of NFs. Thus, MSC P43 is indispensable in maintaining axonal integrity. Its dysfunction may underlie the NF disorganization and axon degeneration associated with motor neuron degenerative diseases.
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hormonal activity of aimp1 P43 for glucose homeostasis
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Sang-gyu Park, Sunghoon Kim, Youngsun Kang, Jin Young Kim, Chang Seok Lee, Woo Je Lee, Ki Up Lee, Young Il YeomAbstract:AIMP1/P43 is known as a cytokine working in the control of angiogenesis, inflammation, and wound healing. Here we report its enrichment in pancreatic α cells and glucagon-like hormonal activity. AIMP1 is secreted from the pancreas upon glucose starvation. Exogenous infusion of AIMP1 increased plasma levels of glucose, glucagon, and fatty acid, and AIMP1-deficient mice showed reduced plasma glucose levels compared with the wild-type mice under fasting conditions. Thus, AIMP1 plays a glucagon-like role in glucose homeostasis.
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the novel cytokine P43 induces il 12 production in macrophages via nf κb activation leading to enhanced ifn γ production in cd4 t cells
Journal of Immunology, 2006Co-Authors: Eugene Kim, Sunghoon Kim, Seung Hyun Kim, Tae Sung KimAbstract:Recently, we determined that P43, an auxiliary factor of mammalian multiaminoacyl-tRNA synthetases, is secreted, and functions as a novel pleiotropic cytokine. In this study, we have attempted to characterize the effects of P43 on the generation of IL-12 in mouse macrophages. P43 was determined to induce significant IL-12 production from mouse macrophages in a dose-dependent manner. The stimulatory effect of P43 on the activation of IL-12p40 promoter was mapped to a region harboring an NF-kappaB binding site. The nuclear extracts from the P43-stimulated macrophages exhibited profound NF-kappaB DNA-binding activity, as determined by the EMSA. In addition, the P43-stimulated IL-12 induction and NF-kappaB DNA-binding activity were significantly suppressed by caffeic acid phenethyl ester and BAY11-7082, both inhibitors of NF-kappaB activation, indicating that P43 induced the production of IL-12 in macrophages mainly via the activation of NF-kappaB. Importantly, P43 increased the level of IFN-gamma production in the Ag-primed lymph node cells, but had no effect on IL-4 levels. The addition of a neutralizing anti-IL-12p40 mAb to the cell cultures resulted in a decrease of the production of P43-enhanced IFN-gamma by the keyhole limpet hemocyanin-primed lymph node cells. Furthermore, coincubation with P43-pretreated macrophages enhanced the production of IFN-gamma by the keyhole limpet hemocyanin-primed CD4+ T cells, thereby indicating that P43 may enhance IFN-gamma expression in CD4+ T cells via the induction of IL-12 production in macrophages. These results indicate that P43 may play an essential role in the development of the Th1 immune responses associated with cancer immunotherapy and protective immunity against intracellular pathogens.
Gerard Cabello - One of the best experts on this subject based on the ideXlab platform.
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Regulation of mitochondrial activity controls the duration of skeletal muscle regeneration in response to injury
Scientific Reports, 2019Co-Authors: L. Pessemesse, Chantal Cabello, Gerard Cabello, Fabienne Cortade, Emilie Blanchet, Lionel Tintignac, Elodie Jublanc, Rémi Demangel, Chamroeun Sar, Francois CasasAbstract:Thyroid hormone is a major regulator of skeletal muscle development and repair, and also a key regulator of mitochondrial activity. We have previously identified a 43 kDa truncated form of the nuclear T3 receptor TR alpha 1 (P43) which stimulates mitochondrial activity and regulates skeletal muscle features. However, its role in skeletal muscle regeneration remains to be addressed. To this end, we performed acute muscle injury induced by cardiotoxin in mouse tibialis in two mouse models where P43 is overexpressed in or depleted from skeletal muscle. The measurement of muscle fiber size distribution at different time point (up to 70 days) upon injury lead us to unravel requirement of the P43 signaling pathway for satellite cells dependent muscle regeneration; strongly delayed in the absence of P43; whereas the overexpression of the receptor enhances of the regeneration process. In addition, we found that satellite cells derived from P43-Tg mice display higher proliferation rates when cultured in vitro when compared to control myoblasts, whereas P43-/- satellites shows reduced proliferation capacity. These finding strongly support that P43 plays an important role in vivo by controling the duration of skeletal muscle regeneration after acute injury, possibly through the regulation of mitochondrial activity and myoblasts proliferation.
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thyroid hormone action the P43 mitochondrial pathway
Methods of Molecular Biology, 2018Co-Authors: Chantal Wrutniakcabello, Francois Casas, Gerard CabelloAbstract:The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial pathway is now well established. The demonstration that TRα1 mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into mitochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones.The use of a T3 photo affinity label derivative (T3-PAL) allowed detecting two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRα1, mitochondrial T3 receptors were identified as truncated TRα1 forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that P43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. In vitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, and transformation. Generation of transgenic mice demonstrated the involvement of this mitochondrial pathway in the determination of muscle phenotype, glucose metabolism, and thermogenesis.
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Thyroid hormone action: The P43 mitochondrial pathway. Methods
2018Co-Authors: Chantal Wrutniak Cabello, Francois Casas, Gerard CabelloAbstract:The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial _pathway is now well established. The demonstration that TR.al mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into ttùtochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones. The use of a T3 photo affinity label derivative (T3-PAL) allowed detectiug two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRal, mitochondrial T3 receptors were identified as truncated T.Ral forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that P43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. In vitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, and transformation. Generation of transgenic mice demonstrated the involve1nent of this mitochondrial pathway in the determination of muscle phenotype, glucose metabolism, and thermogenesis.
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Mice lacking the P43 mitochondrial T3 receptor become glucose intolerant and insulin resistant during aging
PLoS ONE, 2013Co-Authors: Christelle Bertrand, Gerard Cabello, E. Blanchet, J. S. Annicotte, L. Pessemesse, Jonathan Levin, L. Fajas, Christine Coudray, Béatrice Chabi, Chantal CabelloAbstract:Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (P43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific P43 invalidation. At 2 months of age, we reported that P43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether P43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking P43 are leaner than wild-type mice. P43-/- mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where P43-/- mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking P43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age P43-/- mice became increasingly glucose intolerant. In addition, if up to 12 months old P43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor P43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.
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Protein sequences involved in the mitochondrial import of the 3,5,3'-L-triiodothyronine receptor P43.
Journal of Cellular Physiology, 2012Co-Authors: Angel Carazo, Francois Casas, L. Pessemesse, Jonathan Levin, Chantal Wrutniak Cabello, Pascal Seyer, Stéphanie Grandemange, Muriel Busson, Gerard CabelloAbstract:The major effect of T3 on mitochondrial activity has been partly explained by the discovery of P43, a T3-dependent transcription factor of the mitochondrial genome. P43 is imported into mitochondria in an atypical manner which is not yet fully understood. Our aim was to characterize the P43 sequences inducing its mitochondrial import, using in organello import experiments with wild-type or mutated proteins and validation in CV1 cells. We find that several sequences define the mitochondrial addressing. Two alpha helices in the C-terminal part of P43 are actual mitochondrial import sequences as fusion to a cytosolic protein induces its mitochondrial translocation. Helix 5 drives the atypical mitochondrial import process, whereas helices 10/11 induce a classical import process. However, despite its inability to drive a mitochondrial import, the N-terminal region of P43 also plays a permissive role as in the presence of the C-terminal import sequences different N-terminal regions determine whether the protein is imported or not. These results can be extrapolated to other mitochondrial proteins related to the nuclear receptor superfamily, devoid of classical mitochondrial import sequences.
Sang-gyu Park - One of the best experts on this subject based on the ideXlab platform.
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hormonal activity of aimp1 P43 for glucose homeostasis
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Sang-gyu Park, Sunghoon Kim, Youngsun Kang, Jin Young Kim, Chang Seok Lee, Woo Je Lee, Ki Up Lee, Young Il YeomAbstract:AIMP1/P43 is known as a cytokine working in the control of angiogenesis, inflammation, and wound healing. Here we report its enrichment in pancreatic α cells and glucagon-like hormonal activity. AIMP1 is secreted from the pancreas upon glucose starvation. Exogenous infusion of AIMP1 increased plasma levels of glucose, glucagon, and fatty acid, and AIMP1-deficient mice showed reduced plasma glucose levels compared with the wild-type mice under fasting conditions. Thus, AIMP1 plays a glucagon-like role in glucose homeostasis.
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aminoacyl trna synthetase interacting multi functional protein P43 is imported to endothelial cells via lipid rafts
Journal of Cellular Biochemistry, 2005Co-Authors: Ji Yeon Lee, Sang-gyu Park, Sung Gil Chi, Ji Hyun Kim, Sunghoon KimAbstract:An aminoacyl-tRNA synthetase subunit, P43, was previously demonstrated to be released from mammalian cells, and to function as an extracellular regulator of both angiogenesis and inflammatory responses (Ko et al., [2001] J Biol Chem, 276; 23028; Park et al.[2002], J Biol Chem 277; 45243). Here, we report that P43 is internalized to the endothelial cells via lipid rafts. Exogenous P43 was co-localized on bovine aorta endothelial cells with cholera toxin B (CTB), which binds to cholesterol-enriched lipid rafts. The P43 was rapidly internalized to the cells, as early as 5 min after binding to the surfaces of the cells. P43 bound to the isolated lipid rafts, and its interaction with the lipid rafts, was prevented by high salt content, but not by detergent. This suggests that ionic bonds are involved in the molecular association of P43 with the lipid rafts. Taken together, we conclude that P43 binds to the endothelial cell surface via lipid rafts.
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the novel cytokine P43 stimulates dermal fibroblast proliferation and wound repair
American Journal of Pathology, 2005Co-Authors: Sang-gyu Park, Hyosook Shin, Young Kee Shin, Yeonsook Lee, Eungchil Choi, Bumjoon Park, Sunghoon KimAbstract:The multifunctional cytokine P43 acts on endothelial and immune cells to control angiogenesis and inflammation. In this report, we describe an additional activity of P43 that specifically promotes fibroblast proliferation and wound repair. In skin wound regions from mice, tumor necrosis factor-α induced P43 expression and secretion from macrophages recruited to the site. P43 also promoted fibroblast proliferation through its 146-amino acid N-terminal domain as revealed by deletion mapping. This P43-induced fibroblast proliferation was mediated by extracellular signal-regulated kinase (Erk). Depletion of endogenous P43 in mice by gene disruption retarded wound repair, whereas exogenous supplementation of recombinant human P43 to the wound area stimulated dermal fibroblast proliferation, collagen production, and wound closure. Thus, we have identified a novel P43 activity involving the stimulation of fibroblast proliferation, which could be applied therapeutically to aid wound repair.
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dose dependent biphasic activity of trna synthetase associating factor P43 in angiogenesis
Journal of Biological Chemistry, 2002Co-Authors: Sang-gyu Park, Youngsun Kang, Young Ha Ahn, Soon Hee Lee, Kwang Rok Kim, Kyuwon Kim, Gou Young Koh, Sunghoon KimAbstract:Mammalian aminoacyl tRNA synthetases form a macromolecular protein complex with three non-enzymatic cofactors. Among these factors, P43 is also secreted to work as a cytokine on endothelial as well as immune cells. Here we investigated the activity of P43 in angiogenesis and determined the related mediators. It promoted the migration of endothelial cells at low dose but induced their apoptosis at high dose. P43 at low concentration activated extracellular signal-regulating kinase, which resulted in the induction and activation of matrix metalloproteinase 9. In contrast, P43 at high concentration activated Jun N-terminal kinase, which mediated apoptosis of endothelial cells. These results suggest that P43 is a novel cytokine playing a dose-dependent biphasic role in angiogenesis.
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signaling pathways for tnf production induced by human aminoacyl trna synthetase associating factor P43
Cytokine, 2002Co-Authors: Heonyong Park, Sang-gyu Park, Younggyu KoAbstract:Abstract The P43 protein is associated with human macromolecular aminoacyl tRNA synthetase complex and secreted to up-regulate diverse proinflammatory genes including TNF. Here we focused on the P43-induced TNF production and determined its responsible signal pathway. The P43-induced TNF production was mediated by the activation of MAPK family members, ERK and p38 MAPK, and by IκB degradation leading to the activation of NFκB. We also studied the upstream molecules for ERK and p38 MAPK by using a variety of inhibitors. The inhibitors for protein kinase C (PKC) and phospholipase C (PLC) prevented the P43-induced TNF production. Interestingly, all of the effective drugs inhibited the ERK activity, while the drugs had no effects on p38 MAPK activity and IκB degradation. Together, the P43-induced TNF production was controlled by NFkB, p38 MAPK, and ERK that is dependent on the activities of PLC and PKC.
Marc Mirande - One of the best experts on this subject based on the ideXlab platform.
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translation initiation from two in frame augs generates mitochondrial and cytoplasmic forms of the P43 component of the multisynthetase complex
Biochemistry, 2009Co-Authors: V F Shalak, Monika Kaminska, Marc MirandeAbstract:In humans, nine aminoacyl-tRNA synthetases form a stable multiprotein complex with the three auxiliary proteins p18, p38, and P43. The N-terminal moiety of P43 is involved in its anchoring to the complex, and its C-terminal moiety has a potent tRNA binding capacity. The P43 component of the complex is also the precursor of P43(ARF), an apoptosis-released factor, and of P43(EMAPII), the endothelial-monocyte activating polypeptide II. Here we identified a new translation product of the gene of P43, which contains nine additional N-terminal amino acid residues. This gene product is targeted to the mitochondria and accounts for 2% of P43 expressed in human cells. The cytoplasmic and mitochondrial species of P43 are produced from the same mRNA by a mechanism of leaky scanning of the AUG codon at position −27, which is in an unfavorable sequence context for translation initiation. The finding that a mitochondrial species of P43 exists in human cells further exemplifies the multifaceted implications of P43 and o...
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characterization of P43 arf a derivative of the P43 component of multiaminoacyl trna synthetase complex released during apoptosis
Journal of Biological Chemistry, 2007Co-Authors: V F Shalak, Ludovic Guigou, Monika Kaminska, Mariepaule Wautier, Jeanluc Wautier, Marc MirandeAbstract:In human, nine aminoacyl tRNA synthetases are associated with the three auxiliary proteins, p18, p38, and P43, to form a stable multiprotein complex. The P43 component, which has a potent tRNA binding capacity, is associated to the complex via its N-terminal moiety. This protein is also the precursor of the endothelial monocyte-activating polypeptide II (P43(EMAPII), corresponding to the C-terminal moiety of P43), a cytokine generated during apoptosis. Here we examined the cellular pathway that, starting from the P43 subunit of the complex, leads to this extracellular cytokine. We identified a new intermediate in this pathway, named P43(ARF) for Apoptosis-released Factor. This intermediate is produced in cellulo by proteolytic cleavage of endogenous P43 and is rapidly recovered in the culture medium. This P43 derivative was purified from the medium of human U937 cells subjected to serum starvation. It contains 40 additional N-terminal amino acid residues as compared with the cytokine P43(EMAPII) and may be generated by a member of the matrix metalloproteinase family. Recombinant P43(ARF) is a monomer in solution and binds tRNA with a Kd of approximately 6 nM, 30-fold lower than that of P43. Highly purified P43(ARF) or P43(EMAPII) do not stimulate the expression of E-selectin by human umbilical vein endothelial cells. Our results suggest that the cleavage of P43 and its cellular delocalization, and thus the release of this tRNA binding subunit from the complex, is one of the molecular mechanisms leading to the shut down of protein synthesis in apoptosis.
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the trna interacting factor P43 associates with mammalian arginyl trna synthetase but does not modify its trna aminoacylation properties
Biochemistry, 2004Co-Authors: Ludovic Guigou, V F Shalak, Marc MirandeAbstract:Arginyl-tRNA synthetase (ArgRS) is one of the nine synthetase components of a multienzyme complex containing three auxiliary proteins as well. We previously established that the N-terminal moiety of the auxiliary protein P43 associates with the N-terminal, eukaryotic-specific polypeptide extension of ArgRS. Because P43 is homologous to Arc1p, a yeast general RNA-binding protein that associates with MetRS and GluRS and plays the role of tRNA-binding cofactor in the aminoacylation reaction, we analyzed the functional significance of P43−ArgRS association. We had previously showed that full-length ArgRS, corresponding to the ArgRS species associated within the multisynthetase complex, and ArgRS with a deletion of 73 N-terminal amino acid residues, corresponding to a free species of ArgRS, both produced in yeast, have similar catalytic parameters (Lazard, M., Kerjan, P., Agou, F., and Mirande, M. (2000) J. Mol. Biol. 302, 991−1004). However, a recent study had suggested that association of P43 to ArgRS reduce...
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the emapii cytokine is released from the mammalian multisynthetase complex after cleavage of its P43 proemapii component
Journal of Biological Chemistry, 2001Co-Authors: V F Shalak, Monika Kaminska, Rita Mitnachtkraus, Peter Vandenabeele, Matthias Clauss, Marc MirandeAbstract:Abstract Endothelial-monocyte-activating polypeptide II (EMAPII) is an inflammatory cytokine released under apoptotic conditions. Its proEMAPII precursor proved to be identical to the auxiliary P43 component of the aminoacyl-tRNA synthetase complex. We show here that the EMAPII domain of P43 is released readily from the complex after in vitro digestion with caspase 7 and is able to induce migration of human mononuclear phagocytes. The N terminus ofin vitro-processed EMAPII coincides exactly with that of the mature cytokine isolated from conditioned medium of fibrosarcoma cells. We also show that P43/proEMAPII has a strong tRNA binding capacity (K D = 0.2 μm) as compared with its isolated N or C domains (7.5 μm and 40 μm, respectively). The potent general RNA binding capacity ascribed to P43/proEMAPII is lost upon the release of the EMAPII domain. This suggests that after onset of apoptosis, the first consequence of the cleavage of P43 is to limit the availability of tRNA for aminoacyl-tRNA synthetases associated within the complex. Translation arrest is accompanied by the release of the EMAPII cytokine that plays a role in the engulfment of apoptotic cells by attracting phagocytes. As a consequence, P43 compares well with a molecular fuse that triggers the irreversible cell growth/cell death transition induced under apoptotic conditions.
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the P43 component of the mammalian multi synthetase complex is likely to be the precursor of the endothelial monocyte activating polypeptide ii cytokine
Journal of Biological Chemistry, 1997Co-Authors: Sophie Quevillon, Fabrice Agou, Jeancharles Robinson, Marc MirandeAbstract:P43 is one of the three auxiliary components invariably associated with nine aminoacyl-tRNA synthetases as a multienzyme complex ubiquitous to all eukaryotic cells from flies to humans. The cDNA encoding the hamster protein was isolated by using mixed oligonucleotides deduced from peptide sequences. The 359-amino acid protein is the hamster homologue of the recently reported murine and human EMAP II cytokine implicated in a variety of inflammatory disorders. The sequence of several proEMAP II proteins suggests that the P43 component of the complex is the precursor of the active mature cytokine after cleavage at a conserved Asp residue. The COOH-terminal moiety of P43 is also homologous to polypeptide domains found in bacterial methionyl- or phenylalanyl-tRNA synthetases and in the yeast Arc1p/G4p1 protein that associates with yeast methionyl-tRNA synthetase. Our results implicate the COOH-terminal moiety of P43 as a RNA binding domain. In the native state, as a component of the multisynthetase complex, P43 may be required for tRNA channeling and, after proteolytic processing occurring in tumor cells, would acquire inflammatory properties possibly related to apoptosis. The release of a truncated P43 from the complex could be involved in mediation of the signaling of tumor cells and stimulation of an acute inflammatory response.
