Saskia Diana Günther

University Hospital Cologne

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Martin Krönke

University of Cologne

Hamid Kashkar

University of Cologne

Lars M. Schiffmann

University Hospital Cologne

Melanie Fritsch

University of Cologne

Jens M. Seeger

University of Cologne

Marie‐Christine Albert

University of Cologne

J Paul Werthenbach

University of Cologne

Oliver Coutelle

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Axel Witt

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Kerstin Brinkmann

Walter and Eliza Hall Institute of Medical Research

Cooperative Institutions

University of Cologne

University Hospital Cologne

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Institute of Medical Microbiology and Hygiene

Klinik und Poliklinik für Psychosomatik und Psychotherapie

Centrum für Integrierte Onkologie

Ruhr University Bochum

LVR-Klinik Köln

Universität Hamburg

Heinrich Heine University Düsseldorf

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Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6

Cell Death and Disease (2015)

Stephan Schüll Saskia Diana Günther Susanne Brodesser J. M. Seeger Bettina Tosetti

Abstract Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the specific alteration of the cytochrome c oxidase (COX), representing a common defect found in mitochondrial diseases, facilitates mitochondrial apoptosis in response to oxidative stress. Our data identified an increased ceramide synthase 6 (CerS6) activity as an important pro-apoptotic response to COX dysfunction induced either by chemical or genetic approaches. The elevated CerS6 activity resulted in accumulation of the pro-apoptotic C 16 : 0 ceramide, which facilitates the mitochondrial apoptosis in response to oxidative stress. Accordingly, inhibition of CerS6 or its specific knockdown diminished the increased susceptibility of COX-deficient cells to oxidative stress. Our results provide new insights into how mitochondrial RC dysfunction mechanistically interferes with the apoptotic machinery. On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction.

Ceramide synthase

Mitochondrial respiratory chain

Apoptosis-inducing factor

Intrinsic apoptosis

10.1038/cddis.2015.62

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Citations (61)

Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide

Nature Microbiology (2019)

Saskia Diana Günther Melanie Fritsch Jens M. Seeger Lars M. Schiffmann Scott J. Snipas

Intracellular parasite

10.1038/s41564-019-0620-5

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Citations (36)

Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through LPS

Saskia Diana Günther

Gram-Negative Bacteria

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Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

Proceedings of the National Academy of Sciences (2017)

Sergii Shydlovskyi Anke Y. Zienert Semra İnce Christine Dovengerds Annika Hohendahl

Significance In the human organism, guanylate-binding proteins (GBPs) are involved in antimicrobial and antiviral activity, but the mechanism of GBPs’ action remains poorly understood. We have discovered that binding of a substrate molecule, GTP, to the enzyme triggers the release of an aforemasked lipid anchor, which results in GBP polymerization on the one hand and in the attachment of GBPs to lipid membranes on the other. Thus, membrane binding of GBPs competes with protein polymerization and, furthermore, leads to the membrane tethering, which could play a role in a clearance of engulfed pathogens from the cell. Altogether, our findings give deeper insights into GBPs’ molecular mechanism in the course of pathogen response.

10.1073/pnas.1620959114

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Citations (62)

Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer

British Journal of Cancer (2018)

Lars M. Schiffmann Melanie Fritsch Florian Gebauer Saskia Diana Günther Neil Stair

Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177− metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.

Infiltration (HVAC)

Hypoxia

10.1038/s41416-018-0198-3

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Citations (63)

CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage

Cell Death and Disease (2020)

Marie‐Christine Albert Kerstin Brinkmann Wojciech Pokrzywa Saskia Diana Günther Martin Krönke

Abstract The BH3-only protein NOXA is a regulator of mitochondrial apoptosis by specifically antagonizing the anti-apoptotic protein MCL-1. Here we show that the E3 ubiquitin ligase CHIP controls NOXA stability after DNA damage. Our findings reveal that CHIP and MCL-1 are binding partners of NOXA and differentially define the fate of NOXA. Whereas NOXA is initially targeted to mitochondria upon MCL-1-binding, CHIP mediates ubiquitylation of cytosolic NOXA and promotes lysosomal degradation of NOXA, which is not bound by MCL-1. Our data indicate that MCL-1 defines NOXA abundance and its pro-apoptotic activity. Increased NOXA levels beyond this threshold are effectively removed by lysosomal protein degradation triggered via CHIP-mediated ubiquitylation. Together, these results shed new light on regulatory circuits controlling DNA damage response and identified the E3 ligase CHIP as a new molecular guardian, which restricts the cytosolic accumulation of NOXA upon genotoxic stress.

10.1038/s41419-020-02923-x

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Citations (9)

Epitope-specific immunity against Staphylococcus aureus coproporphyrinogen III oxidase

npj Vaccines (2021)

Alexander Klimka Sonja Mertins Anne Kristin Nicolai Liza Marie Rummler Paul G. Higgins

Abstract Staphylococcus aureus represents a serious infectious threat to global public health and a vaccine against S. aureus represents an unmet medical need. We here characterise two S. aureus vaccine candidates, coproporphyrinogen III oxidase (CgoX) and triose phosphate isomerase (TPI), which fulfil essential housekeeping functions in heme synthesis and glycolysis, respectively. Immunisation with rCgoX and rTPI elicited protective immunity against S. aureus bacteremia. Two monoclonal antibodies (mAb), CgoX-D3 and TPI-H8, raised against CgoX and TPI, efficiently provided protection against S. aureus infection. MAb-CgoX-D3 recognised a linear epitope spanning 12 amino acids (aa), whereas TPI-H8 recognised a larger discontinuous epitope. The CgoX-D3 epitope conjugated to BSA elicited a strong, protective immune response against S. aureus infection. The CgoX-D3 epitope is highly conserved in clinical S. aureus isolates, indicating its potential wide usability against S. aureus infection. These data suggest that immunofocusing through epitope-based immunisation constitutes a strategy for the development of a S. aureus vaccine with greater efficacy and better safety profile.

10.1038/s41541-020-00268-2

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Citations (16)

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Nature Communications (2020)

Lars M. Schiffmann J Paul Werthenbach F. Heintges-Kleinhofer J. M. Seeger Melanie Fritsch

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

Reprogramming

Bioenergetics

10.1038/s41467-020-17472-2

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Citations (54)

Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

Nature (2019)

Melanie Fritsch Saskia Diana Günther Robin Schwarzer Marie‐Christine Albert Fabian Schorn

Pyroptosis

Caspase 8

Knockout mouse

10.1038/s41586-019-1770-6

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Citations (772)