RESUMO
In the nineteenth and early twentieth centuries bones were an essential raw material for the German chemical industry, vital to the production of fertilizer, glue, gelatine, soap and other products. As most of this material was imported, the German school system during the "Third Reich" took the utilisation of bones as an example to illustrate the relevance of the four-year plan of 1936 and its policy of economic self-sufficiency. The school children were encouraged to collect bones from domestic sources and bring them to the collecting points in the schools. Several NS-institutions developed a variety of teaching aids and materials to support school education on this economically and politically important topic. Focussing on the example of bone-utilisation, this paper examines the messages and intentions of these educational materials. It also demonstrates how even apparently ideologically unbiased school subjects, such as chemistry, were instrumentalised for the political indoctrination of the pupils.
RESUMO
K63- and Met1-linked ubiquitylation are crucial posttranslational modifications for TNF receptor signaling. These non-degradative ubiquitylations are counteracted by deubiquitinases (DUBs), such as the enzyme CYLD, resulting in an appropriate signal strength, but the regulation of this process remains incompletely understood. Here, we describe an interaction partner of CYLD, SPATA2, which we identified by a mass spectrometry screen. We find that SPATA2 interacts via its PUB domain with CYLD, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of the LUBAC component HOIP SPATA2 is required for the recruitment of CYLD to the TNF receptor signaling complex upon TNFR stimulation. Moreover, SPATA2 acts as an allosteric activator for the K63- and M1-deubiquitinase activity of CYLD In consequence, SPATA2 substantially attenuates TNF-induced NF-κB and MAPK signaling. Conversely, SPATA2 is required for TNF-induced complex II formation, caspase activation, and apoptosis. Thus, this study identifies SPATA2 as an important factor in the TNF signaling pathway with a substantial role for the effects mediated by the cytokine.
Assuntos
NF-kappa B/metabolismo , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Sistemas CRISPR-Cas , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular , Enzima Desubiquitinante CYLD , Técnicas de Inativação de Genes , Marcação de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Ligação Proteica , Proteínas/genética , Proteínas Supressoras de Tumor/deficiência , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Glycogen synthase kinase 3 (GSK-3) is involved in various signaling pathways controlling metabolism, differentiation and immunity, as well as cell death and survival. GSK-3 targets transcription factors, regulates the activity of metabolic and signaling enzymes, and controls the half-life of proteins by earmarking them for degradation. GSK-3 is unique in its mode of substrate recognition and the regulation of its kinase activity, which is repressed by pro-survival phosphoinositide 3-kinase (PI3K)-AKT signaling. In turn, GSK-3 exhibits pro-apoptotic functions when the PI3K-AKT pathway is inactive. Nevertheless, as GSK-3 is crucially involved in many signaling pathways, its role in cell death regulation is not uniform, and in some situations it promotes cell survival. In this Commentary, we focus on the various aspects of GSK-3 in the regulation of cell death and survival. We discuss the effects of GSK-3 on the regulation of proteins of the BCL-2 family, through which GSK-3 exhibits pro-apoptotic activity. We also highlight the pro-survival activities of GSK-3, which are observed in the context of nuclear factor κB (NFκB) signaling, and we discuss how GSK-3, by impacting on cell death and survival, might play a role in diseases such as cancer.