Research
Special Issue: Immunopeptidomics
The Effect of Interferons on Presentation of Defective Ribosomal Products as HLA Peptides

https://doi.org/10.1016/j.mcpro.2021.100105Get rights and content
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Highlights

  • Degradation products of surplus subunits are often presented as HLA peptides.

  • Interferons increase degradation and presentation of such defective products.

  • Dynamic SILAC facilitates identification of such HLA peptides.

  • This cellular pathway provides alert to the immune system about viral infections.

Abstract

A subset of class I major histocompatibility complex (MHC)-bound peptides is produced from immature proteins that are rapidly degraded after synthesis. These defective ribosomal products (DRiPs) have been implicated in early alert of the immune system about impending infections. Interferons are important cytokines, produced in response to viral infection, that modulate cellular metabolism and gene expression patterns, increase the presentation of MHC molecules, and induce rapid degradation of proteins and cell-surface presentation of their derived MHC peptides, thereby contributing to the battle against pathogen infections. This study evaluated the role of interferons in the induction of rapid degradation of DRiPs to modulate the repertoire of DRiP-derived MHC peptides. Cultured human breast cancer cells were treated with interferons, and the rates of synthesis and degradation of cellular protein and their degradation products were determined by LC-MS/MS analysis, following the rates of incorporation of heavy stable isotope–labeled amino acids (dynamic stable isotope labeling by amino acids in cell culture, dynamic SILAC) at several time points after the interferon application. Large numbers of MHC peptides that incorporated the heavy amino acids faster than their source proteins indicated that DRiP peptides were abundant in the MHC peptidome; interferon treatment increased by about twofold their relative proportions in the peptidome. Such typical DRiP-derived MHC peptides were from the surplus subunits of the proteasome and ribosome, which are degraded because of the transition to immunoproteasomes and a new composition of ribosomes incorporating protein subunits that are induced by the interferon. We conclude that degradation of surplus subunits induced by the interferon is a major source for DRiP–MHC peptides, a phenomenon relevant to coping with viral infections, where a rapid presentation of MHC peptides derived from excess viral proteins may help alert the immune system about the impending infection.

Keywords

MHC peptidome
HLA peptidome
dynamic SILAC
interferon
defective ribosomal products–DRiPs

Abbreviations

CCT
chaperonin-containing T-complex
DRiPs
defective ribosomal products
ER
endoplasmic reticulum
H/L
heavy-to-light
HLA
human leukocyte antigen
IFN
interferon
OSiPs
orphan subunit products
SILAC
stable isotope labeling by amino acids in cell culture
TAP
transporter associated with antigen processing

Cited by (0)

These authors contributed equally to this work.