The impact of misfolding versus targeted degradation on the efficiency of the MHC class I-restricted antigen processing.
Evidence suggests that most epitopes presented by MHC class I molecules are derived from those newly synthesized proteins that are defective due to errors during manufacture. We examined epitope production from model cytosolic and exocytic proteins modified in various ways. Substrates containing a degradation targeting sequence demonstrated very rapid turnover and enhanced epitope production, as was the case for substrate retargeted from endoplasmic reticulum to cytosol. For less radical alterations, including point mutation and deletion and elimination of glycosylation sites, despite detectable changes in folding, half-life was only moderately decreased and there were no significant increases in epitope production. Puromycin, which causes premature termination of protein synthesis, also had no impact upon epitope production. It appears that most defective proteins are not rapidly dispensed with and the targeting of most nascent proteins for Ag processing is not tied to quality control.
Golovina
Tatiana N
TN
Department of Microbiology and Immunology, Jefferson Medical College and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Morrison
Susan E
SE
Eisenlohr
Laurence C
LC
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005089:Exocytosis / Q000235:genetics / Q000276:immunology; D005260:Female; D014644:Genetic Variation; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010454:Peptide Termination Factors / Q000502:physiology; D017510:Protein Folding
D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D009698:Nucleoproteins; D010454:Peptide Termination Factors