Islet stress, degradation and autoimmunity

Abstract

β-cell destruction in type 1 diabetes (T1D) results from the effect of inflammation and autoimmunity. In response to inflammatory signals, islet cells engage adaptive mechanisms to restore and maintain cellular homeostasis. Among these mechanisms, the unfolded protein response (UPR) leads to a reduction of the general protein translation rate, increased production of endoplasmic reticulum chaperones and the initiation of degradation by activation of the ER associated degradation pathway (ERAD) in which newly synthetized proteins are ubiquitinylated and processed through the proteasome. This adaptive phase is also believed to play a critical role in the development of autoimmunity by the generation of neoantigens. While we have previously investigated the effect of stress on transcription, translation and post-translational events as possible source for neoantigens, the participation of the degradation machinery, yet crucial in the generation of antigenic peptides, remains to be investigated in the context of T1D pathology. In this review, we will describe the relation between the unfolded protein response and the Ubiquitin Proteasome System (UPS) and address the role of the cellular degradation machinery in the generation of antigens. Learning from tumour immunology, we propose how these processes may unmask β-cells by triggering the generation of aberrant peptides recognized by the immune cells.

Keywords: ER stress; autoimmunity; neoantigen; proteasome; β-cell.

Figure 1

Schematic representation of preproinsulin processing. In normal environment, following cleavage of the signal peptide, proinsulin is targeted to the secretory pathway and further maturated in insulin and C‐peptide in secretory granules (green arrow). Under stress (red arrows), translation, post‐translational modifications, UPR and UPS contribute independently or synergistically to the generation of T1D autoantigenic peptides

Figure 2

Scheme of the different types of 20S proteasomes. The β subunits of the standard proteasome (β1, β2 and β5) are expressed in all cells. Upon stress, some or all β subunits are substituted by their induced counterparts (β1i, β2i and β5i), composing the intermediate and immunoproteasome. APCs express immunoproteasomes constantly. Cortical thymic epithelial cells express a unique type of β5 subunit, indicated as β5t. The 20S cores can assemble, on 1 or both ends, with a variety of regulatory proteins, among them 19S and 11S were implicated in the antigen presentation process. Targets of the proteasome inhibitors Bortezomib and PR‐957 are indicated