Innovating Works

UPSmeetMet

Financiado
Ubiquitin-Proteasome System crosstalk with Metabolism
Cellular metabolites are essential components of life processes, and their import, biosynthesis, and enzymatic conversion are regulated by a wealth of pathways. The ubiquitin-proteasome system (UPS) plays a major role in ensuring... Cellular metabolites are essential components of life processes, and their import, biosynthesis, and enzymatic conversion are regulated by a wealth of pathways. The ubiquitin-proteasome system (UPS) plays a major role in ensuring that key metabolic regulators are maintained at proper levels, to control concentrations of ions, carbohydrates, amino acids, cofactors, and lipids. In particular, the activities and localization of critical ubiquitination enzymes (E3 ligases) and the proteasome must be tightly regulated to ensure that degradation is restricted to proteins that are unwanted, superfluous, or toxic, while sparing those proteins needed for ongoing metabolic functions. Nonetheless, we have limited knowledge of fundamental structural and cellular mechanisms underlying this regulation, and the extent of crosstalk between E3 ligases and metabolic signals. The main aim of this proposal is to decipher molecular principles underlying crosstalk between ubiquitination and metabolites at large. By using time-resolved cryo EM, single-molecule biophysics, cell-based mutagenesis screens and functional studies, we will provide insights into how E3 ligases regulate key mediators of glucose, ion, and lipid homeostasis (Aim 1). To further increase knowledge of the breadth and depth of crosstalk between metabolic pathways and the UPS, we will use our toolkit of E3 ligases and probes to define regulatory interactions between a wide swath of metabolites and E3 ligases, and to identify E3s activated upon switches in metabolic conditions (Aim 2). Moreover, we will explore how E3 ligases and proteasomes are reorganized at an ultrastructural level inside cells to respond to starvation or nutrient-rich conditions (Aim 3). Taken together, these interdisciplinary approaches will establish a framework to translate conceptual and technical advances across molecular, structural, cell biological and systems levels, to broadly illuminate coordination between metabolic signals and the UPS. ver más
30/09/2028
MPG
2M€
Duración del proyecto: 65 meses Fecha Inicio: 2023-04-24
Fecha Fin: 2028-09-30

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-04-24
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG: ERC ADVANCED GRANTS
Cerrada hace 2 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
MAXPLANCKGESELLSCHAFT ZUR FORDERUNG DER WISSE... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5