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1.
Oxysterols direct immune cell migration via EBI2 总被引:1,自引:0,他引:1
Hannedouche S Zhang J Yi T Shen W Nguyen D Pereira JP Guerini D Baumgarten BU Roggo S Wen B Knochenmuss R Noël S Gessier F Kelly LM Vanek M Laurent S Preuss I Miault C Christen I Karuna R Li W Koo DI Suply T Schmedt C Peters EC Falchetto R Katopodis A Spanka C Roy MO Detheux M Chen YA Schultz PG Cho CY Seuwen K Cyster JG Sailer AW 《Nature》2011,475(7357):524-527
Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response. 相似文献
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Dawson MA Prinjha RK Dittmann A Giotopoulos G Bantscheff M Chan WI Robson SC Chung CW Hopf C Savitski MM Huthmacher C Gudgin E Lugo D Beinke S Chapman TD Roberts EJ Soden PE Auger KR Mirguet O Doehner K Delwel R Burnett AK Jeffrey P Drewes G Lee K Huntly BJ Kouzarides T 《Nature》2011,478(7370):529-533
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Carsten Lundby Jose A. L. Calbet Paul Robach 《Cellular and molecular life sciences : CMLS》2009,66(22):3615-3623
Hypoxia refers to environmental or clinical settings that potentially threaten tissue oxygen homeostasis. One unique aspect
of skeletal muscle is that, in addition to hypoxia, oxygen balance in this tissue may be further compromised when exercise
is superimposed on hypoxia. This review focuses on the cellular and molecular responses of human skeletal muscle to acute
and chronic hypoxia, with emphasis on physical exercise and training. Based on published work, it is suggested that hypoxia
does not appear to promote angiogenesis or to greatly alter oxidative enzymes in skeletal muscle at rest. Although the HIF-1
pathway in skeletal muscle is still poorly documented, emerging evidence suggests that muscle HIF-1 signaling is only activated
to a minor degree by hypoxia. On the other hand, combining hypoxia with exercise appears to improve some aspects of muscle
O2 transport and/or metabolism. 相似文献
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Greenway MJ Andersen PM Russ C Ennis S Cashman S Donaghy C Patterson V Swingler R Kieran D Prehn J Morrison KE Green A Acharya KR Brown RH Hardiman O 《Nature genetics》2006,38(4):411-413
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration. 相似文献
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D Vilchez L Boyer I Morantte M Lutz C Merkwirth D Joyce B Spencer L Page E Masliah WT Berggren FH Gage A Dillin 《Nature》2012,489(7415):304-308
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Jiaping Han Carsten Blawert Junjie Yang Xiaopeng Lu Jin Hu Mikhail L. Zheludkevich 《自然科学进展(英文版)》2019,29(1):94-102
The rolling of metal sheet often leads to strong contamination of the resulting surface. The present work reports the effects of the surface contamination remaining after rolling of AZ31 Mg alloy on plasma electrolytic oxidation(PEO) treatment of the resulting sheet material. Results indicate that most of the contaminants on the surface of as-rolled AZ31 Mg alloy are removed in the early stages of PEO process. The contaminations slightly influence the phase composition of PEO coating. Non-uniform distribution of contaminations results in aggregation of pores on the surface of PEO samples. On the bare substrate the contaminations are responsible for poor wear and corrosion resistance but final PEO coatings reveals similar performance on contaminated substrate compared to the abraded one. A self-cleaning property of the PEO and possibility of one step process,avoiding pre-cleaning stages, is suggested. 相似文献
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José A. L. Calbet Paul Robach Carsten Lundby 《Cellular and molecular life sciences : CMLS》2009,66(22):3601-3613
Maximal cardiac output is reduced in severe acute hypoxia but also in chronic hypoxia by mechanisms that remain poorly understood.
In theory, the reduction of maximal cardiac output could result from: (1) a regulatory response from the central nervous system,
(2) reduction of maximal pumping capacity of the heart due to insufficient coronary oxygen delivery prior to the achievement
of the normoxic maximal cardiac output, or (3) reduced central command. In this review, we focus on the effects that acute
and chronic hypoxia have on the pumping capacity of the heart, particularly on myocardial contractility and the molecular
responses elicited by acute and chronic hypoxia in the cardiac myocytes. Special emphasis is put on the cardioprotective effects
of chronic hypoxia. (Part of a multi-author review.) 相似文献
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Sayuri Suzuki Annette Lis Carsten Schmitz Reinhold Penner Andrea Fleig 《Cellular and molecular life sciences : CMLS》2018,75(16):3069-3078
The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic α-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growth. TRPM7 channels are negatively regulated through G-protein-coupled receptor-stimulation, either by reducing cellular cyclic adenosine monophosphate (cAMP) or depleting phosphatidylinositol bisphosphate (PIP2) levels in the plasma membrane. We here identify that heterologous overexpression of human TRPM7-K1648R mutant will lead to disruption of protease or purinergic receptor-induced calcium release. The disruption occurs at the level of Gq, which requires intact TRPM7 kinase phosphorylation activity for orderly downstream signal transduction to activate phospholipase (PLC)β and cause calcium release. We propose that this mechanism may support limiting GPCR-mediated calcium signaling in times of insufficient cellular ATP supply. 相似文献
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Katherine Brandao Francina Deason-Towne Xiaoyun Zhao Anne-Laure Perraud Carsten Schmitz 《Cellular and molecular life sciences : CMLS》2014,71(24):4853-4867
The channel kinases TRPM6 and TRPM7 are both members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels and the only known fusions of an ion channel pore with a kinase domain. TRPM6 and TRPM7 form functional, tetrameric channel complexes at the plasma membrane by heteromerization. TRPM6 was previously shown to cross-phosphorylate TRPM7 on threonine residues, but not vice versa. Genetic studies demonstrated that TRPM6 and TRPM7 fulfill non-redundant functions and that each channel contributes uniquely to the regulation of Mg2+ homeostasis. Although there are indications that TRPM6 and TRPM7 can influence each other’s cellular distribution and activity, little is known about the functional relationship between these two channel-kinases. In the present study, we examined how TRPM6 kinase activity influences TRPM7 serine phosphorylation, intracellular trafficking, and cell surface expression of TRPM7, as well as Mg2+-dependent cellular growth. We found TRPM7 serine phosphorylation via the TRPM6 kinase, but no TRPM6 serine phosphorylation via the TRPM7 kinase. Intracellular trafficking of TRPM7 was altered in HEK-293 epithelial kidney cells and DT40 B cells in the presence of TRPM6 with intact kinase activity, independently of the availability of extracellular Mg2+, but TRPM6/7 surface labeling experiments indicate comparable levels of the TRPM6/7 channels at the plasma membrane. Furthermore, using a complementation approach in TRPM7-deficient DT40 B-cells, we demonstrated that wild-type TRPM6 inhibited cell growth under hypomagnesic cell culture conditions in cells co-expressing TRPM6 and TRPM7; however, co-expression of a TRPM6 kinase dead mutant had no effect—a similar phenotype was also observed in TRPM6/7 co-expressing HEK-293 cells. Our results provide first clues about how heteromer formation between TRPM6 and TRPM7 influences the biological activity of these ion channels. We show that TRPM6 regulates TRPM7 intracellular trafficking and TRPM7-dependent cell growth. All these effects are dependent upon the presence of an active TRPM6 kinase domain. Dysregulated Mg2+-homeostasis causes or exacerbates many pathologies. As TRPM6 and TRPM7 are expressed simultaneously in numerous cell types, understanding how their relationship impacts regulation of Mg2+-uptake is thus important knowledge. 相似文献