Quinet, GrégoireXolalpa, WendyReyes-Garau, DianaProfitós-Pelejà, NúriaAzkargorta, MikelCeccato, LaurieGonzalez-Santamarta, MariaMarsal, MariaAndilla, JordiAillet, FabienneBosch, FrancescElortza, FelixLoza-Alvarez, PabloSola, BrigitteCoux, OlivierMatthiesen, RuneMatthiesen, RuneRoué, GaëlRodriguez, Manuel S.2022-03-142022-03-142022-02-012072-6694PURE: 42051362PURE UUID: 2158af6c-d910-478c-a692-040f73948d4cScopus: 85124958813WOS: 000763741100001http://hdl.handle.net/10362/134490Funding Information: Funding: This work was supported at early stages by Spanish MINECO, CTQ2011–27874 grant. M.G.-S. is a fellow of the UbiCODE project funded by the EU’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 765445.Protein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy-lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at the level of lysosome-fusion revealed a constitutive activation of proteaphagy and accumulation of proteasome subunits within autophagosomes in different MCL cell lines with acquired or natural resistance to BTZ. Inhibition of the autophagy receptor p62/SQSTM1 upon verteporfin (VTP) treatment disrupted proteaphagosome assembly, reduced co-localization of proteasome subunits with autophagy markers and negatively impacted proteasome activity. Finally, the silencing or pharmacological inhibition of p62 restored the apoptosis threshold at physiological levels in BTZ-resistant cells both in vitro and in vivo. In total, these results demonstrate for the first time a proteolytic switch from the ubiquitin-proteasome system (UPS) to ALS in B-cell lymphoma refractory to proteasome inhibition, pointing out a crucial role for proteaphagy in this phenomenon and paving the way for the design of alternative therapeutic venues in treatment-resistant tumors.26047138engApoptosisAutophagyProteasome inhibitorTUBEsUbiquitin proteomeVerteporfinOncologyCancer ResearchSDG 3 - Good Health and Well-beingjournal article10.3390/cancers14040923https://www.scopus.com/pages/publications/85124958813