Dr Stéphan CLAVEL

Research team

Cancer, Metabolism and Environment (CAMEEN)

Ubiquitination and cell signalling : from muscle biochemistry to organoid

Abstract

In the cell, the level of each protein is determined by the ratio between synthesis and degradation rate. The regulation of protein half-life is essential to cell homeostasis. Indeed, many proteins with short half-lives have regulatory functions (transcription factors, cell cycle controllers, receptors) that allow the fine tuning of cellular function to environmental stimuli. In eukaryotic cells, two main pathways mediate protein degradation: the ubiquitin-proteasome pathway and lysosomal proteolysis. While the lysosomal pathway is responsible for the degradation of internalized proteins by endocytosis and the degradation of cellular organelles, the ubiquitin-proteasome system is the major pathway for selective protein degradation. The ubiquitin-proteasome pathway is a sequential process in which ubiquitin molecules bind to "target" proteins. The poly-ubiquitinated proteins are then recognized and degraded by a multi-catalytic enzymatic complex called proteasome. During my career, I first studied the effects of environmental cues (exercise and polyunsaturated fatty acids) on the subunit composition and proteolytic activities of the proteasome in skeletal muscle. Then, I studied the regulation of protein ubiquitination in muscle cells. I demonstrated the role of stress kinases on the transcriptional regulation of the ubiquitin-proteasome pathway in muscle atrophy. Next, I undertook the functional characterization of a "ubiquitin like" protein called UBTD1. In this work, we showed that UBTD1, through the process of ubiquitination, regulates the main cellular pathway of mechanical signal transduction (YAP) as well as EGF receptor signaling. Currently, I am pursuing the characterization of UBTD1 and developing scientific projects that aim to better understand how mechanical signals control the proliferation of adult stem cells notably via the regulation of nucleic acid synthesis pathways. In the meantime, using "organoid" as a model, I develop processes and tools dedicated to in vitrotesting of chemical compounds cytotoxicity.

Keywords

Ubiquitin, proteasome, organoid, signalling, mechanobiology, adult stem cells