The proteasome, a complex multimeric structure strictly implicated in cell protein degradation, has gained the status of privileged drug target since its functional involvement in relevant pathways ruling the cell life, such as cell cycle, transcription and protein quality control, and the recent marketing of bortezomib as proteasome inhibitor for anti-cancer therapy. The marine γ-hydroxybutenolide terpenoid petrosaspongiolide M has been recently discovered as new proteasome inhibitor through a chemical proteomic approach and in cell biological assays. In this study a deep investigation has been carried out on the molecular mechanism of interaction of petrosaspongiolide M with the immunoproteasome, a proteasomal variant mainly involved in the immune responses. The results define a picture in which petrosaspongiolide M exerts its inhibitory activity by binding the active sites in the inner core of the immunoproteasome and/or covalently linking a Lys residue at the proteasome core/11S activator particle interface. Moreover, petrosaspongiolide M is also able to impair autophagy, a complementary pathway involved in protein degradation and cross-talking with the proteasome system. On this basis, petrosaspongiolide M could represent an interesting molecule for its propensity to modulate intracellular proteolysis through a dual inhibition of the immunoproteasome and autophagy.
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