title: Mechanistic insights on petrosaspongiolide M inhibitory effects on immunoproteasome and autophagy.
abstract: 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.
authors: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
authors: Maria Chiara
authors: MC
authors: Monti
authors: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
authors: Luigi
authors: L
authors: Margarucci
authors: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
authors: Raffaele
authors: R
authors: Riccio
authors: School of Biosciences and Biotechnology, University of Camerino, via Gentile III da Varano, 62032 Camerino, Italy.
authors: Laura
authors: L
authors: Bonfili
authors: School of Biosciences and Biotechnology, University of Camerino, via Gentile III da Varano, 62032 Camerino, Italy.
authors: Matteo
authors: M
authors: Mozzicafreddo
authors: School of Biosciences and Biotechnology, University of Camerino, via Gentile III da Varano, 62032 Camerino, Italy. Electronic address: annamaria.eleuteri@unicam.it.
authors: Anna Maria
authors: AM
authors: Eleuteri
authors: Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. Electronic address: casapullo@unisa.it.
authors: Agostino
authors: A
authors: Casapullo
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000187:drug effects / Q000276:immunology; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry* / Q000187:drug effects / Q000276:immunology; D059748:Proteolysis / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D061988:Proteasome Inhibitors; D021122:Protein Subunits; C118309:petrosaspongiolide m; D009828:Oleanolic Acid; D046988:Proteasome Endopeptidase Complex
keywords: Autophagy; Mass spectrometry; Proteasome inhibitor