Institute of Molecular Health science

Zürich, Switzerland

Institute of Molecular Health science

Zürich, Switzerland
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Garstkiewicz M.,University of Zürich | Strittmatter G.E.,University of Zürich | Grossi S.,University of Zürich | Sand J.,University of Zürich | And 4 more authors.
European Journal of Immunology | Year: 2017

The transcription factor Nrf2 regulates the expression of genes required for protection from xenobiotic and oxidative stress. Under normal conditions Nrf2 is constantly degraded upon ubiquitination, mediated by the Nrf2 inhibitor Keap1. Inflammasomes represent stress-induced protein complexes. They are critically involved in acute and chronic inflammation through caspase-1-mediated activation of pro-inflammatory cytokines. Here, we demonstrate that Nrf2 is a positive regulator of the NLRP3 inflammasome. In contrast, Nrf2-activating compounds, including the anti-inflammatory drug dimethyl fumarate (DMF), inhibit inflammasome activation. Both effects are independent of the transcriptional activity of Nrf2 and, at least in part, not interdependent. On the other hand, NLRP3 inflammasome activation induces a rapid and partly caspase-1- and Keap1-independent degradation of Nrf2. These data argue against a simultaneous activation of both stress-related pathways. Finally, we provide evidence that the cross-regulation of both pathways is controlled by a physical interaction between the Nrf2/Keap1 and NLRP3 complexes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Freimann R.,Eawag - Swiss Federal Institute of Aquatic Science and Technology | Freimann R.,ETH Zurich | Freimann R.,Institute of Molecular Health science | Burgmann H.,Eawag - Swiss Federal Institute of Aquatic Science and Technology | And 2 more authors.
ISME Journal | Year: 2013

Glaciated alpine floodplains are responding quickly to climate change through shrinking ice masses. Given the expected future changes in their physicochemical environment, we anticipated variable shifts in structure and ecosystem functioning of hyporheic microbial communities in proglacial alpine streams, depending on present community characteristics and landscape structures. We examined microbial structure and functioning during different hydrologic periods in glacial (kryal) streams and, as contrasting systems, groundwater-fed (krenal) streams. three catchments were chosen to cover an array of landscape features, including interconnected lakes, differences in local geology and degree of deglaciation. Community structure was assessed by automated ribosomal intergenic spacer analysis and microbial function by potential enzyme activities. We found each catchment to contain a distinct bacterial community structure and different degrees of separation in structure and functioning that were linked to the physicochemical properties of the waters within each catchment. Bacterial communities showed high functional plasticity, although achieved by different strategies in each system. Typical kryal communities showed a strong linkage of structure and function that indicated a major prevalence of specialists, whereas krenal sediments were dominated by generalists. With the rapid retreat of glaciers and therefore altered ecohydrological characteristics, lotic microbial structure and functioning are likely to change substantially in proglacial floodplains in the future. the trajectory of these changes will vary depending on contemporary bacterial community characteristics and landscape structures that ultimately determine the sustainability of ecosystem functioning. © 2013 International Society for Microbial Ecology All rights reserved.

Schafer M.,Institute of Molecular Health science | Willrodt A.-H.,Institute of Molecular Health science | Kurinna S.,Institute of Molecular Health science | Link A.S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 14 more authors.
EMBO Molecular Medicine | Year: 2014

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis. © 2014 The Authors.

Hell M.P.,Institute of Molecular Health science | Duda M.,Institute of Molecular Health science | Weber T.C.,ETH Zurich | Moch H.,University of Zürich | Krek W.,Institute of Molecular Health science
Cancer Research | Year: 2014

The von Hippel-Lindau (VHL) tumor suppressor protein pVHL is commonly mutated in clear cell renal cell carcinoma (ccRCC) and has been implicated in the control of multiple cellular processes that might be linked to tumor suppression, including promoting proper spindle orientation and chromosomal stability. However, it is unclear whether pVHL exerts these mitotic regulatory functions in vivo as well. Here, we applied ischemic kidney injury to stimulate cell division in otherwise quiescent mouse adult kidneys. We show that in the short term (5.5 days after surgery), Vhl-deficient kidney cells demonstrate both spindle misorientation and aneuploidy. The spindle misorientation phenotype encompassed changes in directed cell division, which may manifest in the development of cystic lesions, whereas the aneuploidy phenotype involved the occurrence of lagging chromosomes but not chromosome bridges, indicative of mitotic checkpoint impairment. Intriguingly, in the long term (4 months after the ischemic insult), Vhl-deficient kidneys displayed a heterogeneous pattern of ccRCC precursor lesions, including cysts, clear cell-type cells, and dysplasia. Together, these data provide direct evidence for a key role of pVHL in mediating oriented cell division and faithful mitotic checkpoint function in the renal epithelium, emphasizing the importance of pVHL as a controller of mitotic fidelity in vivo. ©2014 American Association for Cancer Research.

Nedialkova L.P.,Max Von Pettenkofer Institute | Nedialkova L.P.,German Center for Infection Research | Denzler R.,ETH Zurich | Denzler R.,Institute of Molecular Health science | And 10 more authors.
PLoS Pathogens | Year: 2014

The host's immune system plays a key role in modulating growth of pathogens and the intestinal microbiota in the gut. In particular, inflammatory bowel disorders and pathogen infections induce shifts of the resident commensal microbiota which can result in overgrowth of Enterobacteriaceae ("inflammation-inflicted blooms"). Here, we investigated competition of the human pathogenic Salmonella enterica serovar Typhimurium strain SL1344 (S. Tm) and commensal E. coli in inflammation-inflicted blooms. S. Tm produces colicin Ib (ColIb), which is a narrow-spectrum protein toxin active against related Enterobacteriaceae. Production of ColIb conferred a competitive advantage to S. Tm over sensitive E. coli strains in the inflamed gut. In contrast, an avirulent S. Tm mutant strain defective in triggering gut inflammation did not benefit from ColIb. Expression of ColIb (cib) is regulated by iron limitation and the SOS response. CirA, the cognate outer membrane receptor of ColIb on colicin-sensitive E. coli, is induced upon iron limitation. We demonstrate that growth in inflammation-induced blooms favours expression of both S. Tm ColIb and the receptor CirA, thereby fuelling ColIb dependent competition of S. Tm and commensal E. coli in the gut. In conclusion, this study uncovers a so-far unappreciated role of inflammation-inflicted blooms as an environment favouring ColIb-dependent competition of pathogenic and commensal representatives of the Enterobacteriaceae family. © 2014 Nedialkova et al.

Rohrl C.,Medical University of Vienna | Rohrl C.,Institute of Molecular Biology and Biochemistry | Eigner K.,Medical University of Vienna | Eigner K.,Institute of Molecular Biology and Biochemistry | And 11 more authors.
Journal of Lipid Research | Year: 2014

Metabolic disorders such as type 2 diabetes cause hepatic endoplasmic reticulum (ER) stress, which affects neutral lipid metabolism. However, the role of ER stress in cholesterol metabolism is incompletely understood. Here, we show that induction of acute ER stress in human hepatic HepG2 cells reduced ABCA1 expression and caused ABCA1 redistribution to tubular perinuclear compartments. Consequently, cholesterol effl ux to apoA-I, a key step in nascent HDL formation, was diminished by 80%. Besides ABCA1, endogenous apoA-I expression was reduced upon ER stress induction, which contributed to reduced cholesterol effl ux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol effl ux, cellular cholesterol levels remained unchanged during ER stress. This was due to impaired de novo cholesterol synthesis by reduction of HMG-CoA reductase activity by 70%, although sterol response element-binding protein-2 activity was induced. In mice, ER stress induction led to a marked reduction of hepatic ABCA1 expression. However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress. Taken together, our data suggest that ER stress in metabolic disorders reduces HDL biogenesis due to impaired hepatic ABCA1 function. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Christinat Y.,Ecole Polytechnique Federale de Lausanne | Christinat Y.,Institute of Molecular Health science | Moret B.M.E.,Ecole Polytechnique Federale de Lausanne
IEEE/ACM Transactions on Computational Biology and Bioinformatics | Year: 2013

Alternative splicing is now recognized as a major mechanism for transcriptome and proteome diversity in higher eukaryotes, yet its evolution is poorly understood. Most studies focus on the evolution of exons and introns at the gene level, while only few consider the evolution of transcripts. In this paper, we present a framework for transcript phylogenies where ancestral transcripts evolve along the gene tree by gains, losses, and mutation. We demonstrate the usefulness of our method on a set of 805 genes and two different topics. First, we improve a method for transcriptome reconstruction from ESTs (ASPic), then we study the evolution of function in transcripts. The use of transcript phylogenies allows us to double the precision of ASPic, whereas results on the functional study reveal that conserved transcripts are more likely to share protein domains than functional sites. These studies validate our framework for the study of evolution in large collections of organisms from the perspective of transcripts; for this purpose, we developed and provide a new tool, TrEvoR. © 2013 IEEE.

Bodak M.,Institute of Molecular Health science | Yu J.,Institute of Molecular Health science | Ciaudo C.,Institute of Molecular Health science
Biomolecular Concepts | Year: 2014

Transposable elements (TEs) are mobile DNA elements that represent almost half of the human genome. Transposition of TEs has been implicated as a source of genome evolution and acquisition of new traits but also as an origin of diseases. The activity of these elements is therefore tightly regulated during the life cycle of each individual, and many recent discoveries involved the genetic and epigenetic mechanisms in their control. In this review, we present recent findings in this field of research, focusing on the case of one specific family of TEs: the long-interspersed nuclear elements-1 (LINE-1 or L1). LINE-1 elements are the most representative class of retrotransposons in mammalian genomes. We illustrate how these elements are conserved between mice and humans, and how they are regulated during the life cycle. Additionally, recent advances in genome-wide sequencing approaches allow us not only to better understand the regulation of LINE-1 but also highlight new issues specifically at the bioinformatics level. Therefore, we discuss the state of the art in analyzing such bioinformatics datasets to identify epigenetic regulators of repeated elements in the human genomes. © De Gruyter 2014.

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