Antigen presentation by major histocompatibility complex (MHC) class I is a constitutive process in all nucleated cells. Antigens are peptides derived from both cellular and foreign proteins, and allow CD8+ T cells to distinguish self from non-self. For immune surveillance to be effective, cells must present a diverse repertoire of peptides derived from their intracellular environment to CD8+ T cells. This proposal describes an approach to characterize a non-canonical translation event, termed cryptic translation, which can direct the synthesis of peptides for MHC class I presenting cells. One type of cryptic translation diverges sharply from conventional protein synthesis since a CUG start codon is decoded with leucine instead of the canonical AUG start codon with methionine. Using toeprinting and analytical centrifugation assays, these investigations will explain on a molecular level how ribosomes decode a CUG start codon using leucine. Cryptic peptides are envisaged to be a diverse subset of antigens that increase the complexity of targets for the immune system. A mechanistic understanding of this process will enable regulation of antigen presentation during immune surveillance and could promote the development of tumor vaccines. ? ? ?
