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121.
Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
Tammo Müller Christin Dewitz Jessica Schmitz Anna Sophia Schröder Jan Hinrich Bräsen Brent R. Stockwell James M. Murphy Ulrich Kunzendorf Stefan Krautwald 《Cellular and molecular life sciences : CMLS》2017,74(19):3631-3645
Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes. 相似文献
122.
Frédéric?Delolme Cyril?Anastasi Lindsay?B.?Alcaraz Valentin?Mendoza Sandrine?Vadon-Le Goff Maya?Talantikite Robin?Capomaccio Jimmy?Mevaere La?titia?Fortin Dominique?Mazzocut Odile?Damour Isabelle?Zanella-Cléon David?J.?S.?Hulmes Christopher?M.?Overall Ulrich?Valcourt Fernando?Lopez-Casillas Catherine?MoaliEmail author 《Cellular and molecular life sciences : CMLS》2015,72(5):1009-1027
The metalloproteinase BMP-1 (bone morphogenetic protein-1) plays a major role in the control of extracellular matrix (ECM) assembly and growth factor activation. Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi: 10.6019/PXD000786. 相似文献
123.
Delous M Baala L Salomon R Laclef C Vierkotten J Tory K Golzio C Lacoste T Besse L Ozilou C Moutkine I Hellman NE Anselme I Silbermann F Vesque C Gerhardt C Rattenberry E Wolf MT Gubler MC Martinovic J Encha-Razavi F Boddaert N Gonzales M Macher MA Nivet H Champion G Berthélémé JP Niaudet P McDonald F Hildebrandt F Johnson CA Vekemans M Antignac C Rüther U Schneider-Maunoury S Attié-Bitach T Saunier S 《Nature genetics》2007,39(7):875-881
Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder. 相似文献
124.
125.
Roscioli T Cliffe ST Bloch DB Bell CG Mullan G Taylor PJ Sarris M Wang J Donald JA Kirk EP Ziegler JB Salzer U McDonald GB Wong M Lindeman R Buckley MF 《Nature genetics》2006,38(6):620-622
We describe mutations in the PML nuclear body protein Sp110 in the syndrome veno-occlusive disease with immunodeficiency, an autosomal recessive disorder of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease. This is the first report of the involvement of a nuclear body protein in a human primary immunodeficiency and of high-penetrance genetic mutations in hepatic veno-occlusive disease. 相似文献
126.
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128.
Jonas Protze Doreen Braun Katrin Manuela Hinz Dorothea Bayer-Kusch Ulrich Schweizer Gerd Krause 《Cellular and molecular life sciences : CMLS》2017,74(12):2299-2318
Monocarboxylate transporter 8 (MCT8) mediates thyroid hormone (TH) transport across the plasma membrane in many cell types. In order to better understand its mechanism, we have generated three new MCT8 homology models based on sugar transporters XylE in the intracellular opened (PDB ID: 4aj4) and the extracellular partly occluded (PDB ID: 4gby) conformations as well as FucP (PDB ID: 3o7q) and GLUT3 (PDB ID: 4zwc) in the fully extracellular opened conformation. T3-docking studies from both sides revealed interactions with His192, His415, Arg445 and Asp498 as previously identified. Selected mutations revealed further transport-sensitive positions mainly at the discontinuous transmembrane helices TMH7 and 10. Lys418 is potentially involved in neutralising the charge of the TH substrate because it can be replaced by charged, but not by uncharged, amino acids. The side chain of Thr503 was hypothesised to stabilise a helix break at TMH10 that undergoes a prominent local shift during the transport cycle. A T503V mutation accordingly affected transport. The aromatic Tyr419, the polar Ser313 and Ser314 as well as the charged Glu422 and Glu423 lining the transport channel have been studied. Based on related sugar transporters, we suggest an alternating access mechanism for MCT8 involving a series of amino acid positions previously and newly identified as critical for transport. 相似文献
129.
Gieger C Radhakrishnan A Cvejic A Tang W Porcu E Pistis G Serbanovic-Canic J Elling U Goodall AH Labrune Y Lopez LM Mägi R Meacham S Okada Y Pirastu N Sorice R Teumer A Voss K Zhang W Ramirez-Solis R Bis JC Ellinghaus D Gögele M Hottenga JJ Langenberg C Kovacs P O'Reilly PF Shin SY Esko T Hartiala J Kanoni S Murgia F Parsa A Stephens J van der Harst P Ellen van der Schoot C Allayee H Attwood A Balkau B Bastardot F Basu S Baumeister SE Biino G Bomba L Bonnefond A Cambien F Chambers JC Cucca F 《Nature》2011,480(7376):201-208
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. 相似文献
130.
科学钻探是现代地球科学研究中一个不可或缺的工具,因为它是直接获得地球深部过程信息的唯一来源,对于我们更好地认识了解我们赖以生存的星球、解决紧迫的社会经济问题具有关键性的作用。国际大陆科学钻探计划(ICDP)始于1996年,2005年在德国波茨坦召开了第二届国际大陆钻探会议。 相似文献