Interferon-γ induces immunoproteasomes and the presentation of MHC I-associated peptides on human salivary gland cells.

Martha E Arellano-Garcia,Simon D Tran,Kaori Misuno,Shen Hu,Thorbald Van Hall

doi:10.1371/journal.pone.0102878

Martha E Arellano-Garcia, Simon D Tran + Show 3 more

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https://doi.org/10.1371/journal.pone.0102878

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Abstract

A prominent histopathological feature of Sjögren's syndrome, an autoimmune disease, is the presence of lymphocytic infiltrates in the salivary and lachrymal glands. Such infiltrates are comprised of activated lymphocytes and macrophages, and known to produce multiple cytokines including interferon-gamma (IFN-γ). In this study, we have demonstrated that IFN-γ strongly induces the expression of immunoproteasome beta subunits (β1i, β2i and β5i) and immunoproteasome activity but conversely inhibits the expression of proteasome beta subunits (β1, β2 and β5) in human salivary gland (HSG) cells. Mass spectrometric analysis has revealed potential MHC I-associated peptides on the HSG cells, including a tryptic peptide derived from salivary amylase, due to IFN-γ stimulation. These results suggest that IFN-γ induces immunoproteasomes in HSG cells, leading to enhanced presentation of MHC I-associated peptides on cell surface. These peptide-presenting salivary gland cells may be recognized and targeted by auto-reactive T lymphocytes. We have also found that lactacystin, a proteasome inhibitor, inhibits the expression of β1 subunit in HSG cells and blocks the IFN-γ-induced expression of β1i and immunoproteasome activity. However, the expression of β2i and β5i in HSG cells is not affected by lactacystin. These results may add new insight into the mechanism regarding how lactacystin blocks the action of proteasomes or immunoproteasomes.

Highlights

Proteasomes are large protein complexes that function to degrade a wide spectrum of proteins involved in the regulation of cellular processes
IFN-c induces the expression of b1i, b2i and b5i in human salivary gland (HSG) cells
Compared to untreated HSG cells, b1i expression increased 2.7, 6, 6.9- or 7-fold (p,0.009) while b5i expression increased 2.1, 2.2, 2.4- or 2.6-fold (p,0.002), respectively, in HSG cells when treated with IFN-c for 24, 48, 72, and 96 hours

Summary

Introduction

Proteasomes are large protein complexes that function to degrade a wide spectrum of proteins involved in the regulation of cellular processes. The two inner rings are composed of seven beta (b) subunits containing active protease-like sites. These proteolytic sites are located on the interior surface of the rings, so that the target protein must enter the central core for degradation. Formation of the 26S proteasome requires the addition of a regulatory cap structure to each end of the four stacked rings. These caps recognize ubiquitinylated proteins, unfold these degradation substrates and thread them into the inner chamber of the proteasome complex where proteolysis takes place

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