A5074186441- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- CRISPR and Genetic Engineering
- Glycosylation and Glycoproteins Research
- Lysosomal Storage Disorders Research
- Lipid Membrane Structure and Behavior
- Calcium signaling and nucleotide metabolism
- Galectins and Cancer Biology
- Protein Degradation and Inhibitors
- Carbohydrate Chemistry and Synthesis
- Polyamine Metabolism and Applications
- Hemophilia Treatment and Research
- Receptor Mechanisms and Signaling
- Pancreatic function and diabetes
- Plant biochemistry and biosynthesis
- Heat shock proteins research
- Iron Metabolism and Disorders
- Plant Molecular Biology Research
- Advanced Proteomics Techniques and Applications
- Complement system in diseases
- RNA regulation and disease
- Protein Kinase Regulation and GTPase Signaling
- Biotin and Related Studies
- Microbial Natural Products and Biosynthesis
Novartis (Switzerland)
2012-2024
Novartis Institutes for BioMedical Research
2014-2021
Pathways Behavioral Services
2009-2012
Novartis (United States)
2012
University of Basel
2003-2010
Université de Montréal
2005
Syngenta (United States)
2001
Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely macroautophagy for growth and survival, suggesting potential therapeutic approach of using autophagy inhibitors based genetic stratification. In this study, we evaluated whether KRAS mutation status predict efficacy inhibition. By profiling 47 cell lines with pharmacological loss-of-function...
The G protein-coupled receptor (GPCR) superfamily represents the most important class of pharmaceutical targets. Therefore, characterization cascades and their ligands is a prerequisite to discovering novel drugs. Quantification agonist-induced second messengers downstream-coupled kinase activities central GPCRs or other pathways that converge on GPCR-mediated signaling. Furthermore, there need for simple, cell-based assays would report direct indirect actions effectors More generally,...
The secretory pathway is composed of membrane compartments specialized in protein folding, modification, transport, and sorting. Numerous transient protein-protein interactions guide the transport-competent proteins through pathway. Here we have adapted yellow fluorescent (YFP)-based fragment complementation assay (PCA) to detect living cells. Fragments YFP were fused homooligomeric cargo-receptor lectin endoplasmic reticulum Golgi intermediate compartment (ERGIC)-53, ERGIC-53-interacting...
Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway requires FIP200, ATG9A, VPS34, TAX1BP1 but lacks involvement ATG8 lipidation machinery constitutes classical macroautophagy. binds directly NCOA4...
SQSTM1 is an adaptor protein that integrates multiple cellular signaling pathways and whose expression tightly regulated at the transcriptional post-translational level. Here, we describe a forward genetic screening paradigm exploiting CRISPR-mediated genome editing coupled to cell selection step by FACS identify regulators of SQSTM1. Through systematic comparison pooled libraries, show CRISPR superior RNAi in identifying known modulators. A genome-wide screen exposed MTOR signalling entire...
Abstract We have undertaken a large-scale genetic screen to identify genes with seedling-lethal mutant phenotype. From screening ~38,000 insertional lines, we identified >500 mutants, completed cosegregation analysis of the insertion and lethal phenotype for >200 molecularly characterized 54 provided detailed description 22 them. Most mutants seem affect chloroplast function because they display altered pigmentation encoding proteins predicted localization. Although high level...
Secretory proteins are exported from the endoplasmic reticulum (ER) by bulk flow and/or receptor-mediated transport. Our understanding of this process is limited because low number identified transport receptors and cognate cargo proteins. In mammalian cells, lectin ER Golgi intermediate compartment 53-kD protein (ERGIC-53) represents best characterized receptor. It assists export a subset glycoproteins including coagulation factors V VIII cathepsin C Z. Here, we report novel screening...
Exit of soluble secretory proteins from the endoplasmic reticulum (ER) can occur by receptor-mediated export as exemplified blood coagulation factors V and VIII. Their efficient secretion requires membrane lectin ER Golgi intermediate compartment protein-53 (ERGIC-53) its luminal interaction partner multiple factor deficiency protein 2 (MCFD2), which form a cargo receptor complex in early pathway. ERGIC-53 also interacts with two lysosomal glycoproteins cathepsin Z C. Here, we tested subunit...
Argyrins, produced by myxobacteria and actinomycetes, are cyclic octapeptides with antibacterial antitumor activity. Here, we identify elongation factor G (EF-G) as the cellular target of argyrin B in bacteria, via resistant mutant selection whole genome sequencing, biophysical binding studies crystallography. Argyrin binds a novel allosteric pocket EF-G, distinct from known EF-G inhibitor antibiotic fusidic acid, revealing new mode protein synthesis inhibition. In eukaryotic cells, was...
Transcription factor EB (TFEB) activates lysosomal biogenesis genes in response to environmental cues. Given implications of impaired TFEB signaling and dysfunction metabolic, neurological, infectious diseases, we aim systematically identify TFEB-directed circuits by examining transcriptional responses subcellular localization stimulation. We reveal that steady-state nuclear is sufficient activate transcription lysosomal, autophagy, innate immunity genes, whereas other targets require higher...
The leguminous-type (L-type) lectin VIP36 localizes to the Golgi apparatus and cycles early in secretory pathway. In vitro, binds high-mannose glycans with a pH optimum of 6.5, value similar luminal apparatus. Although sugar-binding properties vitro have been characterized detail, function intact cell remains unclear as no convincing glycoprotein cargo has identified. Here, we used yellow fluorescent protein (YFP) fragment complementation identify interaction partners VIP36. By screening...
The mammalian target of rapamycin (mTOR) is regulated by oncogenic growth factor signals and plays a pivotal role in controlling cellular metabolism, survival. Everolimus (RAD001) an allosteric mTOR inhibitor that has shown marked efficacy certain cancers but unable to completely inhibit activity. ATP-competitive inhibitors such as NVP-BEZ235 can block rapamycin-insensitive readouts have entered clinical development anti-cancer agents. Here, we show the degree which RAD001 BEZ235 be...
Abstract Gene and compound functions are often interrogated by perturbation. However, we have limited methods to capture associated phenotypes in an unbiased holistic manner. Here, describe Fluopack screening as a novel platform enabling the profiling of subcellular with Our approach leverages imaging panel fluorescent chemical probes survey cellular processes high throughput fashion. Segmentation-free, whole image analysis applied images identifies revealing distinct upon perturbation,...
VPS34 is a key regulator of endomembrane dynamics and cargo trafficking, essential in cultured cell lines mice. To better characterize the role growth, we performed unbiased line profiling studies with selective inhibitor PIK-III identified RKO as VPS34-dependent cellular model. Pooled CRISPR screen presence revealed endolysosomal genes genetic suppressors. Dissecting alterations transcriptional profiling, found induction hypoxia response cholesterol biosynthesis signatures. Mechanistically,...
Background: In the classical form of α1-antitrypsin deficiency (ATD), misfolded Z (ATZ) variant accumulates in endoplasmic reticulum (ER) liver cells.A gain-of-function proteotoxic mechanism is responsible for chronic disease a sub-group homozygotes.Proteostatic response pathways, including conventional ERAD and autophagy, have been proposed as mechanisms that allow cellular adaptation presumably protection from phenotype.Recent studies concluded distinct lysosomal pathway called ERLAD...