A Systematic Interrogation of MHC Class I Antigen Presentation Identifies Constitutive and Compensatory Protein Degradation Pathways

Protein degradation products are constitutively presented as peptide antigens by MHC Class I. While hypervariability of Class I genes is known to tremendously impact antigen presentation, whether differential function of protein degradation pathways (comprising >1000 genes) could alter antigen generation remains poorly understood apart from a few model substrates. In this study, we introduce normalization methods for quantitative antigen mass spectrometry and confirm that most Class I antigens are dependent on ubiquitination and proteasomal degradation. Remarkably, many antigens derived from mitochondrial inner membrane proteins are not. Additionally, we find that atypical antigens can arise from compensatory protein degradation pathways, such as an increase in mitochondrial and membrane protein antigen presentation upon proteasome inhibition. Notably, incomplete inhibition of protein degradation pathways may have clinical utility in cancer immunotherapy, as evidenced by appearance of novel antigens upon partial proteasome inhibition.