title: ER stress affects processing of MHC class I-associated peptides.
abstract: BACKGROUND
  Viral infection and neoplastic transformation trigger endoplasmic reticulum (ER) stress. Thus, a large proportion of the cells that must be recognized by the immune system are stressed cells. Cells respond to ER stress by launching the unfolded protein response (UPR). The UPR regulates the two key processes that control major histocompatibility complex class I (MHC I)-peptide presentation: protein synthesis and degradation. We therefore asked whether and how the UPR impinges on MHC I-peptide presentation.
  
  
  RESULTS
  We evaluated the impact of the UPR on global MHC I expression and on presentation of the H2Kb-associated SIINFEKL peptide. EL4 cells stably transfected with vectors coding hen egg lysozyme (HEL)-SIINFEKL protein variants were stressed with palmitate or exposed to glucose deprivation. UPR decreased surface expression of MHC I but did not affect MHC I mRNA level nor the total amount of intracellular MHC I proteins. Impaired MHC I-peptide presentation was due mainly to reduced supply of peptides owing to an inhibition of overall protein synthesis. Consequently, generation of H2Kb-SIINFEKL complexes was curtailed during ER stress, illustrating how generation of MHC I peptide ligands is tightly coupled to ongoing protein synthesis. Notably, the UPR-induced decline of MHC I-peptide presentation was more severe when the protein source of peptides was localized in the cytosol than in the ER. This difference was not due to changes in the translation rates of the precursor proteins but to increased stability of the cytosolic protein during ER stress.
  
  
  CONCLUSIONS
  Our results demonstrate that ER stress impairs MHC I-peptide presentation, and that it differentially regulates expression of ER- vs. cytosol-derived peptides. Furthermore, this work illustrates how ER stress, a typical feature of infected and malignant cells, can impinge on cues for adaptive immune recognition.
authors.affiliation: Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada. dp.granados@umontreal.ca
authors.forename: Diana P
authors.initials: DP
authors.lastname: Granados
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Tanguay
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Hardy
authors.forename: Etienne
authors.initials: E
authors.lastname: Caron
authors.forename: Danielle
authors.initials: D
authors.lastname: de Verteuil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017951:Antigen Presentation; D045744:Cell Line, Tumor; D002645:Chickens; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009113:Muramidase / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017510:Protein Folding; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D006183:H-2 Antigens; C110366:OVA-8; D010168:Palmitates; D010446:Peptide Fragments; D014415:Tunicamycin; D010047:Ovalbumin; C421864:hen egg lysozyme; D009113:Muramidase