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Ezra Burstein - One of the best experts on this subject based on the ideXlab platform.
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Image_5_Epithelial Na+ Channel: Reciprocal Control by COMMD10 and Nedd4-2.TIFF
2018Co-Authors: Adam W. Ware, Ezra Burstein, Tanya T. Cheung, Sahib Rasulov, Fiona J. McdonaldAbstract:Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney’s long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC. COMMD1, 3 and 9 have been shown to down-regulate ENaC, most likely through Nedd4-2, however, the other COMMD family members remain uncharacterized. To investigate the effects of the COMMD10 protein on ENaC trafficking and function, the interaction of ENaC and COMMD10 was confirmed. Stable COMMD10 knockdown in Fischer rat thyroid epithelia decreased ENaC current and this decreased current was associated with increased Nedd4-2 protein, a known negative regulator of ENaC. However, inhibition of Nedd4-2’s ubiquitination of ENaC was only able to partially rescue the observed reduction in current. Stable COMMD10 knockdown results in defects both in endocytosis and recycling of transferrin suggesting COMMD10 likely interacts with multiple pathways to regulate ENaC and therefore could be involved in the long-term control of blood pressure.
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Epithelial Na+ Channel: Reciprocal Control by COMMD10 and Nedd4-2
'Frontiers Media SA', 2018Co-Authors: Adam W. Ware, Ezra Burstein, Tanya T. Cheung, Sahib Rasulov, Fiona J. McdonaldAbstract:Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney’s long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC. COMMD1, 3 and 9 have been shown to down-regulate ENaC, most likely through Nedd4-2, however, the other COMMD family members remain uncharacterized. To investigate the effects of the COMMD10 protein on ENaC trafficking and function, the interaction of ENaC and COMMD10 was confirmed. Stable COMMD10 knockdown in Fischer rat thyroid epithelia decreased ENaC current and this decreased current was associated with increased Nedd4-2 protein, a known negative regulator of ENaC. However, inhibition of Nedd4-2’s ubiquitination of ENaC was only able to partially rescue the observed reduction in current. Stable COMMD10 knockdown results in defects both in endocytosis and recycling of transferrin suggesting COMMD10 likely interacts with multiple pathways to regulate ENaC and therefore could be involved in the long-term control of blood pressure
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Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function
Frontiers Media S.A., 2018Co-Authors: Shani Ben Shlomo, Odelia Mouhadeb, Keren Cohen, Inbal Farkash, Shlomo Gruber, Nitsan Maharshak, Zamir Halpern, Ezra BursteinAbstract:Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD
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Video_1_Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function.MP4
2018Co-Authors: Odelia Mouhadeb, Nathan Gluck, Ezra Burstein, Shani Ben Shlomo, Keren Cohen, Inbal Farkash, Shlomo Gruber, Nitsan Maharshak, Zamir Halpern, Chen VarolAbstract:Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.
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Data_Sheet_1_Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function.docx
2018Co-Authors: Odelia Mouhadeb, Nathan Gluck, Ezra Burstein, Shani Ben Shlomo, Keren Cohen, Inbal Farkash, Shlomo Gruber, Nitsan Maharshak, Zamir Halpern, Chen VarolAbstract:Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.
Cisca Wijmenga - One of the best experts on this subject based on the ideXlab platform.
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the copper metabolism murr1 domain protein 1 COMMD1 modulates the aggregation of misfolded protein species in a client specific manner
PLOS ONE, 2014Co-Authors: Willianne I M Vonk, Paulina Bartuzi, Dick Jaarsma, Vaishali Kakkar, Ruud Berger, Marten H Hofker, Leo W J Klomp, Cisca Wijmenga, Harm H KampingaAbstract:The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the copper-transporters ATP7B and ATP7A, RELA and HIF-1α). Recently, we established an interaction between the Cu/Zn superoxide dismutase 1 (SOD1) and COMMD1, resulting in a decreased maturation and activation of SOD1. Mutations in SOD1, associated with the progressive neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), cause misfolding and aggregation of the mutant SOD1 (mSOD1) protein. Here, we identify COMMD1 as a novel regulator of misfolded protein aggregation as it enhances the formation of mSOD1 aggregates upon binding. Interestingly, COMMD1 co-localizes to the sites of mSOD1 inclusions and forms high molecular weight complexes in the presence of mSOD1. The effect of COMMD1 on protein aggregation is client-specific as, in contrast to mSOD1, COMMD1 decreases the abundance of mutant Parkin inclusions, associated with Parkinson’s disease. Aggregation of a polyglutamine-expanded Huntingtin, causative of Huntington’s disease, appears unaltered by COMMD1. Altogether, this study offers new research directions to expand our current knowledge on the mechanisms underlying aggregation disease pathologies.
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the copper transporting capacity of atp7a mutants associated with menkes disease is ameliorated by COMMD1 as a result of improved protein expression
Cellular and Molecular Life Sciences, 2012Co-Authors: Willianne I M Vonk, Ruud Berger, Cisca Wijmenga, Prim De Bie, Catharina G K Wichers, Peter V E Van Den Berghe, Rozemarijn Van Der Plaats, Leo W J KlompAbstract:Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P1B-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30°C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process.
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liver specific COMMD1 knockout mice are susceptible to hepatic copper accumulation
PLOS ONE, 2011Co-Authors: Willianne I M Vonk, Paulina Bartuzi, Ruud Berger, Leo W J Klomp, Cisca Wijmenga, Niels J Kloosterhuis, Prim De Bie, Catharina G K Wichers, S Haywood, Bart Van De SluisAbstract:Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of COMMD1 deficiency on hepatic copper metabolism in mice. Liver-specific COMMD1 knockout mice (COMMD1Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in COMMD1Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. COMMD1Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon COMMD1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, COMMD1Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in COMMD1Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in COMMD1Δhep mice could be detected. Despite the absence of hepatocellular toxicity in COMMD1Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis.
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cu zn superoxide dismutase maturation and activity are regulated by COMMD1
Journal of Biological Chemistry, 2010Co-Authors: Willianne I M Vonk, Ruud Berger, Cisca Wijmenga, Bart Van De Sluis, Leo W J KlompAbstract:The maturation and activation of the anti-oxidant Cu,Zn superoxide dismutase (SOD1) are highly regulated processes that require several post-translational modifications. The maturation of SOD1 is initiated by incorporation of zinc and copper ions followed by disulfide oxidation leading to the formation of enzymatically active homodimers. Our present data indicate that homodimer formation is a regulated final step in SOD1 maturation and implicate the recently characterized copper homeostasis protein COMMD1 in this process. COMMD1 interacts with SOD1, and this interaction requires CCS-mediated copper incorporation into SOD1. COMMD1 does not regulate disulfide oxidation of SOD1 but reduces the level of SOD1 homodimers. RNAi-mediated knockdown of COMMD1 expression results in a significant induction of SOD1 activity and a consequent decrease in superoxide anion concentrations, whereas overexpression of COMMD1 exerts exactly the opposite effects. Here, we identify COMMD1 as a novel protein regulating SOD1 activation and associate COMMD1 function with the production of free radicals.
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COMMD1 promotes pvhl and o2 independent proteolysis of hif 1α via hsp90 70
PLOS ONE, 2009Co-Authors: Leo W J Klomp, Cisca Wijmenga, Bart Van De Sluis, Arjan J Groot, Jeroen F Vermeulen, Elsken Van Der Wall, Paul J Van Diest, Marc VooijsAbstract:Background: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-kappa B signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for COMMD1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. Principal Findings: Here we characterized the mechanism by which COMMD1 regulates HIF-1 alpha protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90b for binding to the NH2-terminal DNA-binding and heterodimerization domain of HIF-1 alpha to regulate HIF-1 alpha stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1 alpha degradation independent of ubiquitin and pVHL. Conclusion/Significance: These data reveal a novel role for COMMD1 in conjunction with HSP90 beta/HSP70 in the ubiquitin and O-2-independent regulation of HIF-1 alpha.
Leo W J Klomp - One of the best experts on this subject based on the ideXlab platform.
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the copper metabolism murr1 domain protein 1 COMMD1 modulates the aggregation of misfolded protein species in a client specific manner
PLOS ONE, 2014Co-Authors: Willianne I M Vonk, Paulina Bartuzi, Dick Jaarsma, Vaishali Kakkar, Ruud Berger, Marten H Hofker, Leo W J Klomp, Cisca Wijmenga, Harm H KampingaAbstract:The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the copper-transporters ATP7B and ATP7A, RELA and HIF-1α). Recently, we established an interaction between the Cu/Zn superoxide dismutase 1 (SOD1) and COMMD1, resulting in a decreased maturation and activation of SOD1. Mutations in SOD1, associated with the progressive neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), cause misfolding and aggregation of the mutant SOD1 (mSOD1) protein. Here, we identify COMMD1 as a novel regulator of misfolded protein aggregation as it enhances the formation of mSOD1 aggregates upon binding. Interestingly, COMMD1 co-localizes to the sites of mSOD1 inclusions and forms high molecular weight complexes in the presence of mSOD1. The effect of COMMD1 on protein aggregation is client-specific as, in contrast to mSOD1, COMMD1 decreases the abundance of mutant Parkin inclusions, associated with Parkinson’s disease. Aggregation of a polyglutamine-expanded Huntingtin, causative of Huntington’s disease, appears unaltered by COMMD1. Altogether, this study offers new research directions to expand our current knowledge on the mechanisms underlying aggregation disease pathologies.
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clusterin and COMMD1 independently regulate degradation of the mammalian copper atpases atp7a and atp7b
Journal of Biological Chemistry, 2012Co-Authors: Stephanie Materia, Leo W J Klomp, Michael A Cater, Julian F B Mercer, Sharon La FontaineAbstract:Abstract ATP7A and ATP7B are copper-transporting P1B-type ATPases (Cu-ATPases) that are critical for regulating intracellular copper homeostasis. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and copper toxicity disorders, Menkes and Wilson diseases, respectively. Clusterin and COMMD1 were previously identified as interacting partners of these Cu-ATPases. In this study, we confirmed that clusterin and COMMD1 interact to down-regulate both ATP7A and ATP7B. Overexpression and knockdown of clusterin/COMMD1 decreased and increased, respectively, endogenous levels of ATP7A and ATP7B, consistent with a role in facilitating Cu-ATPase degradation. We demonstrate that whereas the clusterin/ATP7B interaction was enhanced by oxidative stress or mutation of ATP7B, the COMMD1/ATP7B interaction did not change under oxidative stress conditions, and only increased with ATP7B mutations that led to its misfolding. Clusterin and COMMD1 facilitated the degradation of ATP7B containing the same Wilson disease-causing C-terminal mutations via different degradation pathways, clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway. Furthermore, endogenous ATP7B existed in a complex with clusterin and COMMD1, but these interactions were neither competitive nor cooperative and occurred independently of each other. Together these data indicate that clusterin and COMMD1 represent alternative and independent systems regulating Cu-ATPase quality control, and consequently contributing to the maintenance of copper homeostasis.
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the copper transporting capacity of atp7a mutants associated with menkes disease is ameliorated by COMMD1 as a result of improved protein expression
Cellular and Molecular Life Sciences, 2012Co-Authors: Willianne I M Vonk, Ruud Berger, Cisca Wijmenga, Prim De Bie, Catharina G K Wichers, Peter V E Van Den Berghe, Rozemarijn Van Der Plaats, Leo W J KlompAbstract:Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P1B-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30°C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process.
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liver specific COMMD1 knockout mice are susceptible to hepatic copper accumulation
PLOS ONE, 2011Co-Authors: Willianne I M Vonk, Paulina Bartuzi, Ruud Berger, Leo W J Klomp, Cisca Wijmenga, Niels J Kloosterhuis, Prim De Bie, Catharina G K Wichers, S Haywood, Bart Van De SluisAbstract:Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of COMMD1 deficiency on hepatic copper metabolism in mice. Liver-specific COMMD1 knockout mice (COMMD1Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in COMMD1Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. COMMD1Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon COMMD1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, COMMD1Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in COMMD1Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in COMMD1Δhep mice could be detected. Despite the absence of hepatocellular toxicity in COMMD1Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis.
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cu zn superoxide dismutase maturation and activity are regulated by COMMD1
Journal of Biological Chemistry, 2010Co-Authors: Willianne I M Vonk, Ruud Berger, Cisca Wijmenga, Bart Van De Sluis, Leo W J KlompAbstract:The maturation and activation of the anti-oxidant Cu,Zn superoxide dismutase (SOD1) are highly regulated processes that require several post-translational modifications. The maturation of SOD1 is initiated by incorporation of zinc and copper ions followed by disulfide oxidation leading to the formation of enzymatically active homodimers. Our present data indicate that homodimer formation is a regulated final step in SOD1 maturation and implicate the recently characterized copper homeostasis protein COMMD1 in this process. COMMD1 interacts with SOD1, and this interaction requires CCS-mediated copper incorporation into SOD1. COMMD1 does not regulate disulfide oxidation of SOD1 but reduces the level of SOD1 homodimers. RNAi-mediated knockdown of COMMD1 expression results in a significant induction of SOD1 activity and a consequent decrease in superoxide anion concentrations, whereas overexpression of COMMD1 exerts exactly the opposite effects. Here, we identify COMMD1 as a novel protein regulating SOD1 activation and associate COMMD1 function with the production of free radicals.
Bart Van De Sluis - One of the best experts on this subject based on the ideXlab platform.
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nuclear COMMD1 is associated with cisplatin sensitivity in ovarian cancer
PLOS ONE, 2016Co-Authors: Alina Fedoseienko, Marten H Hofker, Bart Van De Sluis, Hylke W. Wieringa, Bea G. A. Wisman, Anna K. L. Reyners, Ate G. J. Van Der Zee, Evelien W Duiker, Marcel A. T. M. Van VugtAbstract:Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients’ survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.
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COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1a via HSP90/70
2016Co-Authors: Bart Van De Sluis, Arjan J Groot, Elsken Van Der Wall, Paul J Van Diest, Jeroen Vermeulen, Leo W. Klomp, Marc VooijsAbstract:Background: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-kB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for COMMD1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. Principal Findings: Here we characterized the mechanism by which COMMD1 regulates HIF-1a protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90b for binding to the NH2-terminal DNA-binding and heterodimerization domain of HIF-1a to regulate HIF-1a stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1a degradation independent of ubiquitin and pVHL. Conclusion/Significance: These data reveal a novel role for COMMD1 in conjunction with HSP90b/HSP70 in the ubiquiti
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Antibody validation and exploratory immunostaining for COMMD1 in human ovarian tumor samples.
2016Co-Authors: Alina Fedoseienko, Marten H Hofker, Bart Van De Sluis, Hylke W. Wieringa, Bea G. A. Wisman, Evelien Duiker, Anna K. L. Reyners, Ate G. J. Van Der Zee, Marcel A. T. M. Van VugtAbstract:(A) Representative immunohistochemical COMMD1 staining in paraffin embedded HEK293T and HeLa cells depleted for COMMD1. (B) HEK293T and HeLa cells were stably silenced for COMMD1 as shown by immunoblotting. (C) Observational immunostainings for COMMD1, including its control IgG1 immunostaining in a consecutive slide, in HGSOC patient samples demonstrating either absent or presence of nuclear COMMD1. (D) Quantification workflow of immunohistochemical COMMD1 staining. Image analysis was performed using the ImageJ-based software package FIJI. DAB staining and hematoxylin staining were deconvoluted and images were subsequently converted into 8-bit gray scale images. Hematoxylin staining was used to define cytoplasm/nucleus boundaries. Vectors were subsequently used to measure DAB staining intensities across cells and quantify nuclear COMMD1 levels in relation to cytoplasmic levels. (B) Three ‘nuclear COMMD1-negative’ (n = 10 cells per tumor sample) and three ‘nuclear COMMD1-positive’ tumor samples were analyzed. Averages and standard deviations are indicated. Relative nuclear COMMD1 levels to cytoplasmic levels are plotted per tumor sample.
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Increased nuclear expression of COMMD1 leads to elevated apoptosis and impaired gene expression in cisplatin treated A2780 cells.
2016Co-Authors: Alina Fedoseienko, Marten H Hofker, Bart Van De Sluis, Hylke W. Wieringa, Bea G. A. Wisman, Evelien Duiker, Anna K. L. Reyners, Ate G. J. Van Der Zee, Marcel A. T. M. Van VugtAbstract:(A) Whole-cell lysates of untreated and 2 μM cisplatin (24 hours) treated A2780 EV and A2780 COMMD1 cells were analyzed by immunoblotting using the indicated antibodies. (B) Relative protein levels of Bcl2, XIAP, BRCA1 were quantified (n = 3) (C) mRNA levels of the indicated genes in non-treated and 2 μM cisplatin (24 hours) treated A2780 COMMD1 cells were determined by qRT-PCR and presented relative to A2780 EV control cells. GAPDH expression was used as an internal control. Average values are presented with SEM. Significance was calculated using the Student's t-test. *: P< 0.05, **: P
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functional understanding of the versatile protein copper metabolism murr1 domain 1 COMMD1 in copper homeostasis
Annals of the New York Academy of Sciences, 2014Co-Authors: Alina Fedoseienko, Paulina Bartuzi, Bart Van De SluisAbstract:Copper is an important cofactor in numerous biological processes in all living organisms. However, excessive copper can be extremely toxic, so it is vital that the copper level within a cell is tightly regulated. The damaging effect of copper is seen in several hereditary forms of copper toxicity in humans and animals. At present, Wilson's disease is the best-described and best-studied copper-storage disorder in humans; it is caused by mutations in the ATP7B gene. In dogs, a mutation in the COMMD1 gene has been found to be associated with copper toxicosis. Using a liver-specific COMMD1 knockout mouse, the biological role of COMMD1 in copper homeostasis has been confirmed. Yet, the exact mechanism by which COMMD1 regulates copper homeostasis is still unknown. Here, we give an overview of the current knowledge and perspectives on the molecular function of COMMD1 in copper homeostasis.
Fiona J. Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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structural insights into the architecture and membrane interactions of the conserved commd proteins
eLife, 2018Co-Authors: Michael D Healy, Fiona J. Mcdonald, Manuela K Hospenthal, Ryan J Hall, Mintu Chandra, Molly Chilton, Vikas A Tillu, Kaien Chen, Dion J Celligoi, Peter J CullenAbstract:The COMMD proteins are a conserved family of proteins with central roles in intracellular membrane trafficking and transcription. They form oligomeric complexes with each other and act as components of a larger assembly called the CCC complex, which is localized to endosomal compartments and mediates the transport of several transmembrane cargos. How these complexes are formed however is completely unknown. Here, we have systematically characterised the interactions between human COMMD proteins, and determined structures of COMMD proteins using X-ray crystallography and X-ray scattering to provide insights into the underlying mechanisms of homo- and heteromeric assembly. All COMMD proteins possess an α-helical N-terminal domain, and a highly conserved C-terminal domain that forms a tightly interlocked dimeric structure responsible for COMMD-COMMD interactions. The COMM domains also bind directly to components of CCC and mediate non-specific membrane association. Overall these studies show that COMMD proteins function as obligatory dimers with conserved domain architectures.
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Image_5_Epithelial Na+ Channel: Reciprocal Control by COMMD10 and Nedd4-2.TIFF
2018Co-Authors: Adam W. Ware, Ezra Burstein, Tanya T. Cheung, Sahib Rasulov, Fiona J. McdonaldAbstract:Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney’s long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC. COMMD1, 3 and 9 have been shown to down-regulate ENaC, most likely through Nedd4-2, however, the other COMMD family members remain uncharacterized. To investigate the effects of the COMMD10 protein on ENaC trafficking and function, the interaction of ENaC and COMMD10 was confirmed. Stable COMMD10 knockdown in Fischer rat thyroid epithelia decreased ENaC current and this decreased current was associated with increased Nedd4-2 protein, a known negative regulator of ENaC. However, inhibition of Nedd4-2’s ubiquitination of ENaC was only able to partially rescue the observed reduction in current. Stable COMMD10 knockdown results in defects both in endocytosis and recycling of transferrin suggesting COMMD10 likely interacts with multiple pathways to regulate ENaC and therefore could be involved in the long-term control of blood pressure.
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Epithelial Na+ Channel: Reciprocal Control by COMMD10 and Nedd4-2
'Frontiers Media SA', 2018Co-Authors: Adam W. Ware, Ezra Burstein, Tanya T. Cheung, Sahib Rasulov, Fiona J. McdonaldAbstract:Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney’s long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC. COMMD1, 3 and 9 have been shown to down-regulate ENaC, most likely through Nedd4-2, however, the other COMMD family members remain uncharacterized. To investigate the effects of the COMMD10 protein on ENaC trafficking and function, the interaction of ENaC and COMMD10 was confirmed. Stable COMMD10 knockdown in Fischer rat thyroid epithelia decreased ENaC current and this decreased current was associated with increased Nedd4-2 protein, a known negative regulator of ENaC. However, inhibition of Nedd4-2’s ubiquitination of ENaC was only able to partially rescue the observed reduction in current. Stable COMMD10 knockdown results in defects both in endocytosis and recycling of transferrin suggesting COMMD10 likely interacts with multiple pathways to regulate ENaC and therefore could be involved in the long-term control of blood pressure
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COMMD1 murr1 reinforces hiv 1 latent infection through iκb α stabilization
Journal of Virology, 2015Co-Authors: Manabu Taura, Fiona J. Mcdonald, Eriko Kudo, Mary Ann Suico, Hiroki Goto, Ryusho Kariya, Kouki Matsuda, Shinichiro Hattori, Kulthida Vaeteewoottacharn, Tsuyoshi ShutoAbstract:The transcription factor NF-κB is important for HIV-1 transcription initiation in primary HIV-1 infection and reactivation in latently HIV-1-infected cells. However, comparative analysis of the regulation and function of NF-κB in latently HIV-1-infected cells has not been done. Here we show that the expression of IκB-α, an endogenous inhibitor of NF-κB, is enhanced by latent HIV-1 infection via induction of the host-derived factor COMMD1/Murr1 in myeloid cells but not in lymphoid cells by using four sets of latently HIV-1-infected cells and the respective parental cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the phosphoinositol 3-kinase (PI3K)–JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Our findings indicate that COMMD1 induction is the NF-κB inhibition mechanism in latently HIV-1-infected cells that contributes to innate immune deficiency and reinforces HIV-1 latency. Thus, COMMD1 might be a double-edged sword that is beneficial in primary infection but not beneficial in latent infection when HIV-1 eradication is considered. IMPORTANCE HIV-1 latency is a major barrier to viral eradication in the era of combination antiretroviral therapy. In this study, we found that COMMD1/Murr1, previously identified as an HIV-1 restriction factor, inhibits the proteasomal degradation of IκB-α by increasing the interaction with IκB-α in latently HIV-1-infected myeloid cells. IκB-α protein was stabilized by COMMD1, which attenuated NF-κB signaling during the innate immune response and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the PI3K-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Thus, the host-derived factor COMMD1 is beneficial in suppressing primary infection but enhances latent infection, indicating that it may be a double-edged sword in HIV-1 eradication.
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COMMD1 and ion transport proteins what is the commection focus on COMMD1 interacts with the cooh terminus of nkcc1 in calu 3 airway epithelial cells to modulate nkcc1 ubiquitination
American Journal of Physiology-cell Physiology, 2013Co-Authors: Fiona J. McdonaldAbstract:over the past decade, COMMD1 (copper metabolism MURR1 domain containing protein 1) has been regularly identified to interact with ion transport proteins. What do we know about COMMD1, and is there a common ion transport regulatory role for COMMD1? COMMD1 is evolutionarily conserved, and codes for a