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Julien Marcoux, laureate of the ANR Young Researchers programme 2019

CNRS Research associate Julien Marcoux receives grant from the ANR Young Researchers programme 2019

 

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ProteasoRegMS - Structural mass spectrometry to study the dialogue between the regulatory mechanisms of proteasome complexes

The main function of the proteasome is to determine the turnover rate of intracellular proteins. Its deregulation has been associated to several neurodegenerative diseases and cancers. Its activity can be tuned by interaction with dedicated regulators, replacement of the standard catalytic subunits and/or by post-translational modifications. The resulting diversity is a real therapeutic challenge as the lack of specificity of the current inhibitors induces deleterious side-effects. Our innovative approach enables to have access to the different combinations of proteoforms present in the cellular extract and to identify the regulators that are specific to certain subtypes of the proteasome complex. The ProteasoRegMS project aims at using structural MS methods to better understand the complex interplay between regulation pathways of the human proteasome in the context of inflammation (IBD and colorectal cancer), as it is known to induce the production of the immunoproteasome. We are confident to identify not only disease-specific proteoforms, but also different interacting partners, that could help to understand the role played by the proteasome in these auto-inflammatory pathologies. Another issue to be addressed is to understand how the insertion of different catalytic subunits can favor the interaction with different regulators using Hydrogen-Deuterium eXchange coupled to MSFinally, we will try to better understand proteasome inhibitionand take advantage of three ligand libraries availableat the institute to screen more than 3,000 molecules and seek for new regulator-specific proteasome inhibitors.