A5078875087- Cell death mechanisms and regulation
- Signaling Pathways in Disease
- RNA Interference and Gene Delivery
- Mitochondrial Function and Pathology
- Heat shock proteins research
- Toxin Mechanisms and Immunotoxins
- Endoplasmic Reticulum Stress and Disease
- Platelet Disorders and Treatments
- Protein Degradation and Inhibitors
- Genetics, Aging, and Longevity in Model Organisms
- ATP Synthase and ATPases Research
- Research on Leishmaniasis Studies
- Peptidase Inhibition and Analysis
- Acute Myeloid Leukemia Research
- Blood Coagulation and Thrombosis Mechanisms
- Complement system in diseases
- PARP inhibition in cancer therapy
- Ion channel regulation and function
- Autophagy in Disease and Therapy
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Computational Drug Discovery Methods
- Metabolism and Genetic Disorders
- Cancer-related Molecular Pathways
- Metabolomics and Mass Spectrometry Studies
- Microtubule and mitosis dynamics
Leipzig University
2021-2024
University of Freiburg
2012-2024
Czech Academy of Sciences, Biology Centre
2015
National Institutes of Health
2011-2012
Max Planck Research Unit for Enzymology of Protein Folding
2005-2012
National Institute of Neurological Disorders and Stroke
2011
Jiangsu Changjiang Electronics Technology (China)
2009
Robert Bosch (India)
2009
Ospedale L. Bonomo
2007
University of Virginia
1992
Platelets have distinct roles in the vascular system that they are major mediator of thrombosis, critical for restoration tissue integrity, and players inflammatory conditions. In close spatiotemporal proximity, complement acts as first line defense against invading microorganisms is a key inflammation. Whereas fluid phase cross-talk between coagulation systems well appreciated, understanding pathophysiological implications such interactions still scant.We analyzed coexpression anaphylatoxin...
Significance Bcl-2 (B-cell lymphoma 2) proteins are key regulators of apoptosis. The recruitment the predominantly cytosolic protein Bax (Bcl-2 associated X, apoptosis regulator) to mitochondria is with mitochondrial outer membrane permeabilization and We report specific interactions between transmembrane domains (TMDs) prosurvival Bcl-x L lymphoma-extra large) proteins. Our results demonstrate that these occur in nonapoptotic human cells participate regulation proteins, introducing concept...
The heterodimeric hypoxia-inducible transcription factors (HIFs) are central regulators of the response to low oxygenation. HIF-α subunits constitutively expressed but rapidly degraded under normoxic conditions. Oxygen-dependent hydroxylation two conserved prolyl residues by prolyl-4-hydroxylase domain-containing enzymes (PHDs) targets for proteasomal destruction. We identified peptidyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as a novel interactor PHD2. Yeast two-hybrid,...
Abstract The pro-apoptotic Bcl-2 protein Bax can permeabilize the outer mitochondrial membrane and therefore commit human cells to apoptosis. is regulated by constant translocation mitochondria retrotranslocation back into cytosol. depends on pro-survival proteins stabilizes inactive Bax. Here we show that shuttles membrane-associated membrane-integral from isolated mitochondria. We further discover porin voltage-dependent anion channel 2 (VDAC2) as essential component platform for...
How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role activation the evolutionarily conserved physiological function NLRP3. Here, we have shown that when cells were challenged simultaneously, was inhibited prevailed. Apoptosis inhibition by structurally diverse activators, including nigericin, imiquimod, extracellular ATP, particles, viruses, not a consequence...
FK506 and FK506-derived inhibitors of the FK506-binding protein (FKBP)-type peptidylprolyl cis/trans-isomerases (PPIase) display potent neuroprotective neuroregenerative properties in various neurodegeneration models, showing importance neuroimmunophilins as targets for treatment acute chronic neurodegenerative diseases. However, PPIase activity targeted by active site-directed ligands remainsed unknown so far. Here we show that neurotrophic FKBP ligands, such GPI1046...
Prolyl-4-hydroxylase domain (PHD) proteins are 2-oxoglutarate and dioxygen-dependent enzymes that mediate the rapid destruction of hypoxia-inducible factor alpha subunits. Whereas PHD1 PHD3 proteolysis has been shown to be regulated by Siah2 ubiquitin E3 ligase-mediated polyubiquitylation proteasomal destruction, protein regulation main oxygen sensor responsible for regulation, PHD2, remained unknown. We recently reported FK506-binding (FKBP) 38 specifically interacts with PHD2 determines...
The human protein Bax sits at a critical regulatory junction of apoptosis, or programmed cell death. exists in equilibrium between cytosolic and mitochondria-associated forms that shifts toward the latter when is activated by proapoptotic proteins. Activated changes conformation, inserts into mitochondrial outer membrane (MOM), oligomerizes, induces MOM permeabilization, causing release cytochrome c , which effectively commits to die. Because apoptosis also basic defense mechanism against...
Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject tight control by Bcl-2 family proteins. We have developed a powerful new technique investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression pro- and anti-apoptotic proteins engineer addiction. On addition targeting BH3 mimetics, mito-primed cells undergo apoptosis rapid synchronous manner. Using this method we...
Molecular chaperones promote the folding and macromolecular assembly of a diverse set 'client' proteins. How ubiquitous chaperone machineries direct their activities towards specific sets substrates is unclear. Through use mouse genetics, imaging quantitative proteomics we uncover that ZMYND10 novel co-chaperone confers specificity for FKBP8-HSP90 complex axonemal dynein clients required cilia motility. Loss perturbs chaperoning heavy chains, triggering broader degradation motor subunits. We...
Abstract Apoptosis acts in defense against microbial infection, and many infectious agents have developed strategies to inhibit host cell apoptosis. The human pathogen Chlamydia trachomatis ( Ctr ) is an obligate intracellular bacterium that strongly inhibits mitochondrial apoptosis of its but there no agreement how the bacteria achieve this. We here provide a molecular analysis chlamydial apoptosis-inhibition infected cells demonstrate block occurs during activation effectors apoptosis, Bak...
Significance Receptor–ligand interactions on the cell surface or intrinsic stress signals can commit mammalian cells to apoptosis. In this study, we discover how hexokinases confer resistance receptor-mediated apoptosis through specific inhibition of B-cell lymphoma 2 (BCL-2) proteins. Hexokinases retrotranslocate activator and effector BCL-2 proteins from mitochondria into cytosol. Hexokinase-dependent protein retrotranslocation protect despite death receptor signaling.
Multiple intracellular receptors of the FK506 binding protein (FKBP) family peptidylprolyl cis/trans-isomerases are potential targets for immunosuppressive drug FK506. Inhibition phosphatase calcineurin (CaN), which has been implicated in FK506-mediated blockade T cell proliferation, was shown to involve a gain function FKBP12/FK506 complex. We studied six human FKBPs contribute CaN inhibition by comparative examination constants respective FK506/FKBP complexes. Interestingly, these form...
FKBP38 is a negative effector of the anti-apoptotic Bcl-2 protein in neuroblastoma cells. The interaction with and enzyme activity depend on prior binding calmodulin-Ca(2+) (CaM-Ca(2+)) at high Ca(2+) concentrations. structure contains three tetratricopeptide repeat (TPR) motifs corresponding to Hsp90 sites other immunophilins. In this study we show that TPR domain interacts C-terminal Hsp90, but only if FKBP38-CaM-Ca(2+) complex preformed. Hence, first example TPR-containing immunophilin...