A5012478165- Autophagy in Disease and Therapy
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Cancer, Hypoxia, and Metabolism
- interferon and immune responses
- RNA Research and Splicing
- DNA Repair Mechanisms
- Cancer-related gene regulation
- Cell death mechanisms and regulation
- SARS-CoV-2 and COVID-19 Research
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
- Cellular transport and secretion
- Neonatal Respiratory Health Research
- Advanced Proteomics Techniques and Applications
- COVID-19 Clinical Research Studies
- DNA and Nucleic Acid Chemistry
- Cancer-related Molecular Pathways
- RNA Interference and Gene Delivery
- Acute Myeloid Leukemia Research
- Extracellular vesicles in disease
- PI3K/AKT/mTOR signaling in cancer
- MicroRNA in disease regulation
Frankfurt Cancer Institute
2019-2025
Goethe University Frankfurt
2017-2025
Cardio-Pulmonary Institute
2019-2025
University Hospital Frankfurt
2018-2025
Universität Ulm
2024
Goethe Institute
2019-2024
German Cancer Research Center
2021-2023
Deutschen Konsortium für Translationale Krebsforschung
2021-2023
Heidelberg University
2021-2023
Fraunhofer Institute for Translational Medicine and Pharmacology
2023
Deposition of proteins aberrant conformation is the hallmark many neurodegenerative diseases. Misfolding normally globular mutant superoxide dismutase-1 (SOD1) a central, early, but poorly understood event in pathogenic cascade leading to familial forms ALS. Here we report that aggregates composed an ALS-causing SOD1 penetrate inside cells by macropinocytosis and rapidly exit macropinocytic compartment nucleate aggregation cytosolic, otherwise soluble, protein. Once initiated,...
The ubiquitin-proteasome system targets many cellular proteins for degradation and thereby controls most processes. Although it is well established that proteasome inhibition lethal, the underlying mechanism unknown. Here, we show results in a lethal amino acid shortage. In yeast, mammalian cells, flies, deleterious consequences of are rescued by supplementation. all three systems, this rescuing effect occurs without noticeable changes levels substrates. scarcity resulting from signal causes...
Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent modifications-5-methylcytosine (m5C) its derivative 5-formylcytosine (f5C) (refs.2-4)-drive translation mitochondrial mRNA to power metastasis. Translation mitochondrially encoded subunits oxidative phosphorylation complex depends on formation m5C at position 34 in tRNAMet. m5C-deficient human...
The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional in the nucleus restore proteostasis1,2. Yet, it remains unclear how information on misfolding stress (MMS) signalled as part of human UPRmt (refs. 3,4). Here, we show that signalling driven release two individual signals cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation precursors cytosol (c-mtProt). Combining...
The outer mitochondrial membrane (OMM) is essential for cellular homeostasis. Yet little known of the mechanisms that remodel it during natural stresses. We found large “SPOTs” (structures positive OMM) emerge Toxoplasma gondii infection in mammalian cells. SPOTs mediated depletion OMM proteins mitofusin 1 and 2, which restrict parasite growth. formation depended on effector TgMAF1 host import receptor TOM70, required optimal proliferation. TOM70 enabled to interact with translocase SAM50....
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson's disease, play essential roles mitophagy through ubiquitination of mitochondria. Cargo E3 ubiquitin ligase is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other units such as ATG9A-integrated vesicles recruited remains unclear. Here, using mammalian cultured cells, we...
Regulation of translation is essential during stress. However, the precise sets proteins regulated by key translational stress responses-the integrated response (ISR) and mTORC1-remain elusive. We developed multiplexed enhanced protein dynamics (mePROD) proteomics, adding signal amplification to dynamic-SILAC multiplexing, enable measuring acute changes in synthesis. Treating cells with ISR/mTORC1-modulating stressors, we showed extensive translatome modulation ∼20% synthesized at highly...
In most cases, macroautophagy/autophagy serves to alleviate cellular stress and acts in a pro-survival manner. However, the effects of autophagy are highly contextual, autophagic cell death (ACD) is emerging as an alternative paradigm (stress- drug-induced) demise. AT 101 ([-]-gossypol), natural compound from cotton seeds, induces ACD glioma cells confirmed here by CRISPR/Cas9 knockout ATG5 that partially, but significantly rescued survival following treatment. Global proteomic analysis...
Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is the cause of current coronavirus disease 19 (COVID-19) pandemic. Protease inhibitors are under consideration as entry that prevent cleavage spike (S) protein by cellular proteases. Herein, we showed protease inhibitor aprotinin (but not SERPINA1/alpha-1 antitrypsin) inhibited SARS-CoV-2 replication in therapeutically achievable concentrations. An analysis proteomics and translatome data indicated associated with a downregulation host...
Abstract A novel coronavirus was recently discovered and termed SARS-CoV-2. Human infection can cause disease 2019 (COVID-19), for which, at this point, over 80,000 cases resulting in 2,500 deaths have been reported 40 countries. SARS-CoV-2 shows some similarities to other coronaviruses. However, treatment options a cellular understanding of are lacking. Here we identify the host cell pathways modulated by SARS-CoV-19 reveal that drugs targeting prevent viral replication human cells. We...
Increasing evidence suggests that induction of lethal macroautophagy/autophagy carries potential significance for the treatment glioblastoma (GBM). In continuation previous work, we demonstrate pimozide and loperamide trigger an ATG5- ATG7 (autophagy related 5 7)-dependent type cell death is significantly reduced with cathepsin inhibitors lipid reactive oxygen species (ROS) scavenger α-tocopherol in MZ-54 GBM cells. Global proteomic analysis after both drugs also revealed increase proteins...
Most mitochondrial proteins are translated in the cytosol and imported into mitochondria. Mutations protein import machinery cause human pathologies. However, a lack of suitable tools to measure uptake across proteome has prevented identification specific affected by perturbation. Here, we introduce mePRODmt, pulsed-SILAC based proteomics approach that includes booster signal increase sensitivity for selectively, enabling global dynamic analysis endogenous cells. We applied mePRODmt...
Abstract Mitophagy is essential to maintain mitochondrial function and prevent diseases. It activates upon mitochondria depolarization, which causes PINK1 stabilization on the outer membrane. Strikingly, a number of conditions, including protein misfolding, can induce mitophagy without loss in membrane potential. The underlying molecular details remain unclear. Here, we report that import, mediated by pre-sequence translocase-associated motor complex PAM, sufficient polarized mitochondria. A...
Autophagy is a catabolic process during which cytosolic material enwrapped in newly formed double-membrane structure called the autophagosome, and subsequently targeted for degradation lytic compartment of cell. The fusion autophagosomes with tightly regulated step involves membrane-bound SNARE proteins. These play crucial role as they promote lipid mixing opposing membranes. Among proteins implicated autophagy, essential protein YKT6 only that evolutionarily conserved from yeast to humans....
The copper-zinc superoxide dismutase-1 (SOD1) is a highly structured protein and, priori, one of the least likely proteins to be involved in misfolding disease. However, more than 140, mostly missense, mutations SOD1 gene cause aggregation affected familial forms amyotrophic lateral sclerosis (ALS). remarkable diversity effects these on properties has suggested that they promote by variety mechanisms. Experimental assessment surface hydrophobicity using sensitive fluorescent-based assay,...