L’inhibition de la dégradation protéasomale causée par l’altération du bon fonctionnement du processus d’ubiquitination influe négativement sur la propagation du norovirus murin
Abstract
The Norovirus, a small non-enveloped single stranded positive-sense RNA virus, that belongs to the Caliciviridae family, is highly contagious and resistant and is a major causal agent of viral gastroenteritis resulting in a high human and socioeconomic cost. Due to a lack of approved therapy options, intensive research effort is on going to better understand the mechanisms of noroviral pathogenesis.Viral entry is known to trigger signals that activate the innate immune system in order to neutralize the pathogen. Ubiquitination is an ATP-dependent multistep posttranslational process, involved in the regulation of the immune response, in which a ubiquitin moiety is added to a substrate. Interestingly, we have measured increased levels of polyubiquitination following mouse norovirus (MNoV) infection in macrophages. Different types of polyubiquitin chains can be formed on a given target’s lysine residue which determines the fate of those proteins. In a first study we have evaluated how the alteration of polyubiquitin chain formation could affect the noroviral life cycle. Using the macrophage cell line Raw264.7, several stable cell lines were generated by overexpressing YFP-Ubiquitin_WT, _K29R, _K48Ror_K63R constructs. All non-WT constructs encode a ubiquitin fusion protein with one lysine mutated into an arginine residue, thus preventing the formation of their respective polyubiquitin chains. Upon infection with the murine norovirus S99 (MNoV_S99) strain, we measured a…
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