Major Histocompatibility Complex (MHC) Class I Processing of the NY-ESO-1 Antigen Is Regulated by Rpn10 and Rpn13 Proteins and Immunoproteasomes following Non-lysine Ubiquitination

• Published in: The Journal of biological chemistry Vol. 291; no. 16; pp. 8805 - 8815
• Main Authors: Golnik, Richard, Lehmann, Andrea, Kloetzel, Peter-Michael, Ebstein, Frédéric
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Antigen Presentation; antigen processing; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; HeLa Cells; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; Humans; Immunology; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Membrane Proteins - genetics; Membrane Proteins - immunology; proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - immunology; protein degradation; RNA-Binding Proteins; tumor immunology; ubiquitin; Ubiquitination - genetics; Ubiquitination - immunology; proteasome; tumor immunology; antigen processing; protein degradation; ubiquitin
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M115.705178

The supply of MHC class I-restricted peptides is primarily ensured by the degradation of intracellular proteins via the ubiquitin-proteasome system. Depending on the target and the enzymes involved, ubiquitination is a process that may dramatically vary in terms of linkages, length, and attachment sites. Here we identified the unique lysine residue at position 124 of the NY-ESO-1 cancer/testis antigen as the acceptor site for the formation of canonical Lys-48-linkages. Interestingly, a lysine-less form of NY-ESO-1 was as efficient as its wild-type counterpart in supplying the HLA-A*0201-restricted NY-ESO-1157–165 antigenic peptide. In fact, we show that the regulation of NY-ESO-1 processing by the ubiquitin receptors Rpn10 and Rpn13 as a well as by the standard and immunoproteasome is governed by non-canonical ubiquitination on non-lysine sites. In summary, our data underscore the significance of atypical ubiquitination in the modulation of MHC class I antigen processing.