β-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1

Diabetes. 2020 Apr;69(4):670-680. doi: 10.2337/db19-0984. Epub 2020 Jan 2.

Abstract

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)-mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / genetics
  • Aminopeptidases / metabolism*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • HEK293 Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Insulin / metabolism*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism*
  • Interferon-gamma / pharmacology
  • Interleukin-1beta / pharmacology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism*
  • Protein Precursors / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Up-Regulation

Substances

  • Insulin
  • Interleukin-1beta
  • MIRN17 microRNA, human
  • MicroRNAs
  • Minor Histocompatibility Antigens
  • Protein Precursors
  • preproinsulin
  • Interferon-gamma
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Aminopeptidases
  • ERAP1 protein, human