A5032033332- Ubiquitin and proteasome pathways
- Cell death mechanisms and regulation
- interferon and immune responses
- NF-κB Signaling Pathways
- Inflammasome and immune disorders
- PARP inhibition in cancer therapy
- Pancreatic function and diabetes
- Diabetes and associated disorders
- Cancer, Hypoxia, and Metabolism
- RNA Research and Splicing
- Toxin Mechanisms and Immunotoxins
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Hippo pathway signaling and YAP/TAZ
- Plant nutrient uptake and metabolism
- Tryptophan and brain disorders
- Lipid Membrane Structure and Behavior
- Neuroendocrine Tumor Research Advances
- PI3K/AKT/mTOR signaling in cancer
- Immune cells in cancer
- Adipokines, Inflammation, and Metabolic Diseases
- Retinal and Optic Conditions
- High Altitude and Hypoxia
- Nuclear Structure and Function
- Lipid metabolism and disorders
University of Cologne
2022-2024
Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
2022-2024
University Hospital Cologne
2023
University College London
2013-2019
CRUK Lung Cancer Centre of Excellence
2013-2018
University of Lausanne
2011-2014
Universidad Nacional de La Plata
2008
SHARPIN regulates immune signaling and contributes to full transcriptional activity prevention of cell death in response TNF vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver splenomegaly, loss Peyer's patches. has been proposed cause the inflammatory phenotype consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis...
Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, SHARPIN, the only known ligase that generates linkages. HOIP catalytically active LUBAC component. Here, we show both constitutive Tie2-Cre-driven deletion lead to aberrant endothelial cell death, resulting in defective vascularization embryonic lethality at midgestation. Ablation tumor necrosis factor receptor 1 (TNFR1) prevents defects, death...
The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion HOIP or (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic pharmacological evidence the lethal HoipE-KO Hoil-1E-KO mice caused TNFR1-induced, caspase-8-mediated apoptosis occurs independently kinase activity RIPK1. In...
The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ligase-1 (HOIL-1), and HOIL-1-interacting (HOIP), is a critical regulator inflammation immunity. This highlighted by the fact that patients with perturbed ubiquitination caused mutations in Hoip or Hoil-1 genes, resulting knockouts these proteins, may simultaneously suffer from immunodeficiency autoinflammation. TLR3 plays crucial, albeit...
The ability to generate appropriate defense responses is crucial for the survival of an organism exposed pathogenesis-inducing insults. However, mechanisms that allow tissues and organs cope with such stresses are poorly understood. Here we show caspase-3-knockout mice or caspase inhibitor-treated were defective in activating antiapoptotic Akt kinase response various chemical environmental causing sunburns, cardiomyopathy, colitis. Defective activation was accompanied by increased cell death...
Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, inflammation. Here, we report an unanticipated cell-death- inflammation-independent function RIPK1 Caspase-8, promoting faithful chromosome alignment in mitosis thereby ensuring genome stability. We find that complexes progressively form cells enter mitosis, peaking at metaphase...
Abstract The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized this process might also or contribute to inflammatory disease lung failure following SARS-CoV-2 infection. To test hypothesis, developed a novel mouse-adapted model (MA20) recapitulates key pathological features of COVID-19. Concomitantly with...
Necroptosis is an inflammatory form of regulated cell death implicated in a range human pathologies, whose execution depends on the poorly understood pseudokinase mixed lineage kinase domain-like (MLKL). Here, we report that splicing-dependent insertion short amino acid sequence C-terminal α-helix (Hc) MLKL abolishes killing activity and creates anti-necroptotic isoform counteracts induced by necroptosis-proficient protein mice humans. We show interaction Hc with previously unrecognized...
Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell can interfere with such cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of substrate Caspase-8. the physiological role cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential for in restraining different pathophysiological scenarios. Mice expressing cleavage-resistant mutant,
Linear ubiquitination is a key posttranslational modification that regulates immune signaling and cell death pathways, notably tumor necrosis factor receptor 1 (TNFR1) signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date the chain assembly complex, which catalytic core component heme‐oxidized iron regulatory protein 2 ligase‐1–interacting (HOIP). To understand underlying mechanisms maintenance liver homeostasis role specifically...
Abstract Cellular inhibitor of apoptosis proteins (cIAPs) are RING‐containing E3 ubiquitin ligases that ubiquitylate receptor‐interacting protein kinase 1 (RIPK1) to regulate TNF signalling. Here, we established mice simultaneously expressing enzymatically inactive cIAP1/2 variants, bearing mutations in the RING domains (cIAP1/2 mutant RING, MutR ). cIap1/2 MutR/MutR died during embryonic development due RIPK1‐mediated apoptosis. While expression kinase‐inactive RIPK1 D138N rescued...
Abstract Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance first-line therapy alternative therapies are urgently required overcome this resistance. In study, we tested the efficacy dinaciclib, an FDA-orphan drug inhibitor cyclin-dependent kinase (CDK) 9, among other CDKs, SCLC. Furthermore, report on a newly...
Receptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and death in response to tumor necrosis factor (TNF) other cytokines. Whereas scaffolding function of RIPK1 is crucial prevent TNF-induced apoptosis necroptosis, its activity required for necroptosis partially apoptosis. Although TNF a proinflammatory cytokine associated with β-cell loss diabetes, mechanism by which induces demise remains unclear.
Lymphotoxin β receptor (LTβR), a member of the TNF superfamily (TNFR-SF), is essential for development and maturation lymphoid organs. In addition, LTβR activation promotes carcinogenesis by inducing proinflammatory secretome. Yet, we currently lack detailed understanding signaling. this study discovered linear ubiquitin chain assembly complex (LUBAC) as previously unrecognized functionally crucial component native signaling (LTβR-SC). Mechanistically, LUBAC-generated chains enable...
Some Sinorhizobium meliloti mutants in genes involved isoleucine, valine, and leucine biosynthesis were previously described as being unable to induce nodule formation on host plants. Here, we present a reappraisal of the interconnection between branched-chain amino acid pathway nodulation process S. meliloti. We characterized symbiotic phenotype seven that are auxotrophic for or two closely related strains, 1021 2011. showed all similarly impaired infection Medicago sativa plant. In most...
The caspase-3-generated RasGAP N-terminal fragment (fragment N) inhibits apoptosis in a Ras-PI3K-Akt-dependent manner. Fragment N protects various cell types, including insulin-secreting cells, against different types of stresses. Whether exerts protective role during the development type 1 diabetes is however not known. Non-obese diabetic (NOD) mice represent well-known model for spontaneous that shares similarities with diseases encountered humans. To assess development, transgene encoding...
Summary Methionine-1 (M1)-linked ubiquitin chains, assembled by the ligase LUBAC and cleaved deubiquitinase OTULIN, are critical regulators of inflammation immune homeostasis. Genetic loss either or OTULIN causes autoinflammatory syndromes, which associated with defects in glycogen lipid metabolism. However, how regulate metabolic signalling remains unknown. Here, we demonstrate that promotes, while restricts, activation key regulator AMP-activated protein kinase (AMPK) cells, mice, human...