<p> The classical model of MHC class I antigen processing prescribes a critical role for the ubiquitin-proteasome system in generating peptides to display for CD8+ T cell surveillance. However, multiple exceptions to this pathway have been described. Using large-scale proteomic methods as well as model experiments, we explore 1) the non-proteasomal enzymes responsible for generating or destroying an influenza virus epitope; 2) the role of ubiquitin-independent antigen processing in shaping the MHC class I peptidome; and 3) the contribution to the MHC class I peptide repertoire of aminoglycoside-induced translational readthrough of stop codons. Our findings indicate a significant role for non-classical MHC class I antigen processing. This includes extra-proteasomal proteases we identify as destroying the influenza epitope NP147-155, as well as an impact from ubiquitin-independent pathways that challenges the centrality of the ubiquitin-proteasome system. Additionally, we demonstrate that the non-standard translational events induced by gentamicin can reveal cryptic MHC class I epitopes, with implications for autoimmunity. These observations suggest a substantial contribution from processes that operate outside of the classically described pathways of MHC class I antigen processing.</p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:3616853 |
| Date | 31 May 2014 |
| Creators | Goodenough, Elliot |
| Publisher | Thomas Jefferson University |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
Page generated in 0.0017 seconds