Pioneer Round of Translation Supplies Peptides for Major Histocompatibility Complex Class I Presentation

Cytotoxic T cells monitor MHC class I complexes on antigen presenting cells for the potential presence of any non-self peptides that could derive from viral infection or cancerous cells. Effective immune surveillance requires that MHC class I molecules display a peptide repertoire on the surface representing all cellular proteins. This ensures that foreign antigens from all sources are presented. How the peptide repertoire can be comprehensive despite the large differences in abundance and stability of individual proteins is not known. The pioneer round of translation is the first round of translation that occurs on newly spliced mRNA. It is associated with nonsense-mediated decay of mRNAs, allowing cells to detect and eliminate the aberrant mRNAs containing premature stop codons. We showed here that the peptide presentation by MHC I molecules was strongly influenced by the pioneer round of translation. Inhibition of the pioneer round of translation by knockdown of CBP80, a nuclear cap-binding protein, reduced peptide presentation by MHC class I molecules on the cell surface without affecting global protein synthesis. On the other hand, introduction of premature stop codons changed mRNA stability without affecting peptide presentation by MHC I on the cell surface. In addition, intronless mRNAs bypassing the pioneer round of translation resulted in reduced MHC I presentation on the cell surface. Furthermore, knockdown of CBP80 led to the deficiency of the cytosolic peptides delivered by the transporter associated with antigen processing (TAP) for the MHC class I pathway. Together, these findings highlight the importance of the pioneer round of translation in deriving peptides to generate a comprehensive display of virtually all endogenous proteins for the immune surveillanc