Description du projet
Décoder le réseau de modifications post-traductionnelles des cellules humaines
Les modifications post-traductionnelles telles que l’ubiquitination sont des altérations chimiques des protéines qui régulent leur structure, leur stabilité et leur fonction. L’ajout de la protéine ubiquitine à d’autres protéines peut marquer ces dernières en vue de leur dégradation, modifier leur activité ou participer à la formation de complexes protéiques qui interviennent dans divers processus cellulaires et voies de signalisation. Le projet DUB-DECODE, financé par le Conseil européen de la recherche, se penche sur les déubiquitylases (DUB), des protéases spécifiques de l’ubiquitine, qui éliminent l’ubiquitine des substrats et régulent la signalisation dépendante de l’ubiquitination. Compte tenu du rôle que jouent les DUB dans la physiologie des mammifères et de leur dérèglement dans les maladies, les chercheurs entendent appréhender les détails de leur fonction dans les cellules humaines et fournir de précieuses informations sur les protéines régulées par les DUB.
Objectif
Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers.
Champ scientifique
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
1165 Kobenhavn
Danemark