The structure and location of SIMP/STT3B account for its prominent imprint on the MHC I immunopeptidome.
Proteins show drastic discrepancies in their contribution to the collection of self-peptides that shape the repertoire of CD8 T cells (MHC I self-immunopeptidome). To decipher why selected proteins are the foremost sources of MHC I-associated self-peptides, we chose to study SIMP/STT3B because this protein generates very high amounts of MHC I-associated peptides in mice and humans. We show that the endoplasmic reticulum (ER)-associated degradation pathway and MHC I processing intersect at SIMP/STT3B. Relevant key features of SIMP/STT3B are its lysine-rich region, its propensity to misfold and its location in the ER membrane in close proximity to the immunoproteasome. Moreover, we show that coupling to SIMP/STT3B can be used to foster MHC I presentation of a selected peptide, here the ovalbumin peptide SIINFEKL. These data yield novel insights into relations between the cell proteome and the MHC I immunopeptidome. They suggest that the contribution of a given protein to the MHC I immunopeptidome results from the interplay of at least three factors: the presence of degrons (degradation signals), the tendency of the protein to misfold and its subcellular localization. Furthermore, they indicate that substrates of the ER-associated degradation pathway may have a prominent imprint on the MHC I self-immunopeptidome.
Caron
Etienne
E
Institute of Research in Immunology and Cancer, University of Montreal, Casier Postal 6128, Succ. Centre-ville, Montreal, Quebec H3C 3J7, Canada.
Charbonneau
Renée
R
Huppé
Gabrielle
G
Brochu
Sylvie
S
Perreault
Claude
C
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000648:ultrastructure; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000648:ultrastructure; D016695:Glycosyltransferases / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006602:Hexosyltransferases; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D017510:Protein Folding; D020543:Proteome / Q000276:immunology*
D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D020543:Proteome; D016695:Glycosyltransferases; D006602:Hexosyltransferases; C551978:STT3B protein, human