title: Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation.
abstract: A significant portion of newly synthesized protein fails to fold properly and is quickly degraded. These defective ribosomal products (DRiPs) are substrates for the ubiquitin-proteasome system (UPS) and give rise to a large fraction of peptides presented by major histocompatibility complex class I molecules (MHCI). Here, we showed that DRiPs are also autophagy substrates, which accumulate upon autophagy inhibition in aggresome-like-induced structures (ALIS). Aggregation is critically depending on p62/SQSTM1, but occurs in the absence of activation of the NRF2 signaling axis and transcriptional regulation of p62/SQSTM1. We demonstrated that autophagy-targeted DRiPs can become UPS substrates and give rise to MHCI presented peptides upon autophagy inhibition. We further demonstrated that autophagy targeting of DRiPs is controlled by NBR1, but not p62/SQSTM1, CHIP or BAG-1. Active autophagy therefore directly modulates MHCI presentation by constantly degrading endogenous defective neosynthesized antigens, which are submitted to at least two distinct quality control mechanisms.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, Marseille, France.
authors.forename: Till
authors.initials: T
authors.lastname: Wenger
authors.forename: Seigo
authors.initials: S
authors.lastname: Terawaki
authors.forename: Voahirana
authors.initials: V
authors.lastname: Camosseto
authors.forename: Ronza
authors.initials: R
authors.lastname: Abdelrassoul
authors.forename: Anna
authors.initials: A
authors.lastname: Mies
authors.forename: Nadia
authors.initials: N
authors.lastname: Catalan
authors.forename: Nuno
authors.initials: N
authors.lastname: Claudio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Clavarino
authors.forename: Aude
authors.initials: A
authors.lastname: de Gassart
authors.forename: Francesca de Angelis
authors.initials: Fde A
authors.lastname: Rigotti
authors.forename: Evelina
authors.initials: E
authors.lastname: Gatti
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D001343:Autophagy / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011691:Puromycin / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C549756:NBR1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D061988:Proteasome Inhibitors; D011506:Proteins; D011993:Recombinant Fusion Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D011691:Puromycin; D046988:Proteasome Endopeptidase Complex