Project description:Metabolic requirements vary during tissue development, but little is known whether and how metabolic rewiring orchestrates lineage differentiation and maturation. We discovered an essential metabolic switch from glutamine catabolism to glutamine synthesis during erythropoiesis. Glutamine synthetase (GS), one of the oldest functioning genes, is induced during terminal maturation to promote detoxification of ammonia generated during heme biosynthesis, which is massively upregulated to support hemoglobin production. Loss of GS in mouse erythroid precursors causes ammonia accumulation, oxidative stress, leading to maturation arrest and apoptosis. In β-thalassemia, GS activity is impaired by protein oxidation, causing glutamate and ammonia accumulation, whereas enforced GS expression alleviates the metabolic and pathologic defects. These results identify an evolutionarily conserved metabolic adaptation that may be leveraged to treat common red cell disorders.
Project description:Synaptic function crucially depends on uninterrupted synthesis and degradation of synaptic proteins. While much has been learned on synaptic protein synthesis, little is known on the routes by which synaptic proteins are degraded. Here we systematically studied how inhibition of the ubiquitin-proteasomal system (UPS) affects the degradation rates of thousands of neuronal and synaptic proteins. We identified a number of proteins, including several proteins related to glutamate receptor trafficking, whose degradation rates were significantly slowed by UPS inhibition. Unexpectedly, however, degradation rates of most synaptic proteins were not significantly affected. Interestingly, many of the differential effects of UPS inhibition were readily explained by a quantitative framework that considered known metabolic turnover rates for the same proteins. In contrast to the limited effects on protein degradation, UPS inhibition profoundly and preferentially suppressed the synthesis of a large number of synaptic proteins. Our findings point to the importance of the UPS in the degradation of certain synaptic proteins, yet indicate that under basal conditions most synaptic proteins might be degraded through alternative pathways.
Project description:Synaptic function crucially depends on uninterrupted synthesis and degradation of synaptic proteins. While much has been learned on synaptic protein synthesis, little is known on the routes by which synaptic proteins are degraded. Here we systematically studied how inhibition of the ubiquitin-proteasomal system (UPS) affects the degradation rates of thousands of neuronal and synaptic proteins. We identified a number of proteins, including several proteins related to glutamate receptor trafficking, whose degradation rates were significantly slowed by UPS inhibition. Unexpectedly, however, degradation rates of most synaptic proteins were not significantly affected. Interestingly, many of the differential effects of UPS inhibition were readily explained by a quantitative framework that considered known metabolic turnover rates for the same proteins. In contrast to the limited effects on protein degradation, UPS inhibition profoundly and preferentially suppressed the synthesis of a large number of synaptic proteins. Our findings point to the importance of the UPS in the degradation of certain synaptic proteins, yet indicate that under basal conditions most synaptic proteins might be degraded through alternative pathways.
Project description:Synaptic function crucially depends on uninterrupted synthesis and degradation of synaptic proteins. While much has been learned on synaptic protein synthesis, little is known on the routes by which synaptic proteins are degraded. Here we systematically studied how inhibition of the ubiquitin-proteasomal system (UPS) affects the degradation rates of thousands of neuronal and synaptic proteins. We identified a number of proteins, including several proteins related to glutamate receptor trafficking, whose degradation rates were significantly slowed by UPS inhibition. Unexpectedly, however, degradation rates of most synaptic proteins were not significantly affected. Interestingly, many of the differential effects of UPS inhibition were readily explained by a quantitative framework that considered known metabolic turnover rates for the same proteins. In contrast to the limited effects on protein degradation, UPS inhibition profoundly and preferentially suppressed the synthesis of a large number of synaptic proteins. Our findings point to the importance of the UPS in the degradation of certain synaptic proteins, yet indicate that under basal conditions most synaptic proteins might be degraded through alternative pathways.
Project description:Transcriptional profiling of marine ammonia oxidizing archaea Nitrosopumilus maritimus cells comparing exponential phase control cells with cells under 24 hours starvation and with cells under recovery after 24 hours starvation. Goal was to determine the effects of global transcriptional responses of N. maritimus cells under ammonia starvation and recovery conditions.