A5041954708- Ubiquitin and proteasome pathways
- Cervical Cancer and HPV Research
- Autophagy in Disease and Therapy
- Peptidase Inhibition and Analysis
- Molecular Biology Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- interferon and immune responses
- Protein Degradation and Inhibitors
- NF-κB Signaling Pathways
- Cancer-related Molecular Pathways
- Genital Health and Disease
- Cell Adhesion Molecules Research
- CRISPR and Genetic Engineering
- Urological Disorders and Treatments
- Prenatal Screening and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Advanced biosensing and bioanalysis techniques
- Animal Virus Infections Studies
- RNA Interference and Gene Delivery
- Parvovirus B19 Infection Studies
- Virus-based gene therapy research
- Viral gastroenteritis research and epidemiology
- T-cell and Retrovirus Studies
- Glycosylation and Glycoproteins Research
Goethe University Frankfurt
2016-2025
University Hospital Frankfurt
2023
Frankfurt Cancer Institute
2022
Mediterranean Institute for Life Sciences
2008
Rudjer Boskovic Institute
1997-2005
Ludwig Cancer Research
2003
Abstract Targeted protein degradation is a pharmacological modality that based on the induced proximity of an E3 ubiquitin ligase and target to promote ubiquitination proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed two separate moieties individually bind ligase, or molecular glues monovalently 1–4 . Here, using orthogonal genetic screening, biophysical characterization structural reconstitution, we...
Deubiquitinase fine-tunes Notch signaling The branching of blood vessels is controlled in part by through receptor proteins. When NOTCH1 binds its ligand DLL4, the intracellular domain (NICD1) cleaved from and works with other proteins to regulate gene transcription. In a screen for that interacted NICD1 human cells culture, Lim et al. identified deubiquitinase USP10. rapidly ubiquitinated degraded cells, but interaction USP10 counteracts ubiquitination stimulates signaling. Genetic...
Abstract Selective autophagy of mitochondria, mitophagy, is linked to mitochondrial quality control and as such critical a healthy organism. We have used CRISPR/Cas9 approach screen human E3 ubiquitin ligases for influence on mitophagy under both basal cell culture conditions upon acute depolarization. identify two cullin‐RING ligase substrate receptors, VHL FBXL4, the most profound negative regulators mitophagy. show that these converge, albeit via different mechanisms, adaptors BNIP3...
The autophagy-lysosome system directs the degradation of a wide variety cargo and is also involved in tumor progression. Here, we show that immunity-related GTPase family Q protein (IRGQ), an uncharacterized to date, acts quality control major histocompatibility complex class I (MHC I) molecules. IRGQ misfolded MHC toward lysosomal through its binding mode GABARAPL2 LC3B. In absence IRGQ, free heavy chains do not only accumulate cell but are transported surface, thereby promoting immune...
CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. src homology 3 domains specifically bind to proline-arginine (PxxxPR) motif Cbl, and this association seems be important for EGF receptor endocytosis. Here, we report identification novel effectors, all containing one or more PxxxPR motifs, that are indispensable their mutual interactions. These effectors include phosphatidyl-inositol phosphatases SHIP-1 synaptojanin...
Selective autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is an important regulator ER remodeling and essential to maintain cellular homeostasis during environmental changes. We recently showed that members FAM134 family play a critical role stress-induced ER-phagy. However, mechanisms on how they are activated remain largely unknown. In this study, we analyze phosphorylation trigger FAM134-driven ER-phagy upon mTOR (mechanistic target rapamycin) inhibition. An unbiased...
Abstract Targeted protein degradation is a pharmacological modality based on the induced proximity of an E3 ubiquitin ligase and target to promote ubiquitination proteasomal degradation. This has been achieved either via bifunctional compounds (PROTACs) composed two separate warheads that individually bind ligase, or molecular glues monovalently 1–4 . Using orthogonal genetic screening, biophysical characterization, structural reconstitution, we investigate mode action BRD2/4 degraders...
Abstract Combinatorial CRISPR-Cas screens have advanced the mapping of genetic interactions, but their experimental scale limits number targetable gene combinations. Here, we describe 3Cs multiplexing, a rapid and scalable method to generate highly diverse uniformly distributed combinatorial CRISPR libraries. We demonstrate that library distribution skew is critical determinant its required screening coverage. By circumventing iterative cloning PCR-amplified oligonucleotides, multiplexing...
Abstract Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, its impairment causes autoimmune diseases cancer. NEDD4-binding protein 1 (N4BP1) is a critical suppressor of cytokine production that acts as regulator innate immune signalling inflammation. However, our current understanding about the molecular properties enable N4BP1 to exert suppressive potential remain limited. Here, we show novel linear ubiquitin reader negatively regulates NFκB by...
Abstract The established role of cytosolic and nuclear inclusions TDP-43 in the pathogenesis neurodegenerative disorders has multiplied efforts to understand mechanisms that control aggregation spurred searches for approaches limiting this process. Formation clearance aggregates are controlled by an intricate interplay cellular proteostasis systems involve post-translational modifications frequently rely on spatial control. We demonstrate attachment ubiquitin-like SUMO2 modifier...
Rpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show C-terminal region binds tetratricopeptide repeat (TPR) domain SGTA, a cytosolic factor implicated in quality control mislocalised membrane proteins (MLPs). The overexpression SGTA results substantial increase steady-state MLP levels, consistent with effect on proteasomal However, this strongly dependent upon interaction component Rpn13....
Background: Sestrin 2 is a redox-dependent repressor of Pdgfrβ signaling and thereby interferes with lung injury repair.Results: positive regulator proteasomal function activates transcription Nrf2-regulated antioxidant genes.Conclusion: component novel 2/Pdgfrβ pathway.Significance: The Sestrin2/Pdgfrβ pathway likely to play role in the pathogenesis chronic obstructive pulmonary disease (COPD).We recently identified protein (Sesn2) as suppressor platelet-derived growth factor receptor β...