ER stress impairs MHC Class I surface expression and increases susceptibility of thyroid cells to NK-mediated cytotoxicity

Abstract

We recently reported that, in thyroid cells, ER stress triggered by thapsigargin or tunicamycin, two well known ER stressing agents, induced dedifferentiation and loss of the epithelial phenotype in rat thyroid cells. In this study, we sought to evaluate if, in thyroid cells, ER stress could affect MHC class I expression and the possible implications of this effect in the alteration of function of natural killer cells, suggesting a role in thyroid pathology. In both, a human line of fetal thyroid cells (TAD-2 cells) and primary cultures of human thyroid cells, thapsigargin and tunicamicin triggered ER stress evaluated by BiP mRNA levels and XBP-1 splicing. In both cell types, TAD-2 cell line and primary cultures, major histocompatibility complex class I (MHC-I) plasmamembrane expression was significantly reduced by ER stress. This effect was accompanied by signs of natural killer activation. Thus, natural killer cells dramatically increased IFN-γ production and markedly increased their cytotoxicity against thyroid cells. Together, these data indicate that ER stress induces a decrease of MHC class I surface expression in thyroid cells, resulting in reduced natural killer-cell self-tolerance.

The Unfolded Protein Response (UPR)-activated Transcription Factor X-box-binding Protein 1 (XBP1) Induces MicroRNA-346 Expression That Targets the Human Antigen Peptide Transporter 1 (TAP1) mRNA and Governs Immune Regulatory Genes

“…Further support for our findings comes from studies indicating alterations in self-antigen and viral peptide presentation during ER stress, but without a complete understanding of the underlying mechanisms (52)(53)(54). Furthermore, it is evident that proper ER homeostasis and TAP function are necessary for the assembly of MHC class I subunits and peptides (41,55).…”

An IFN-γ–stimulated ATF6–C/EBP-β–signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy

“…Indeed, IFN-γ has been reported to induce ER stress in oligodendrocytes, although the mechanisms are unclear (24). Thyroid cells undergoing ER stress stimulate IFN-γ production by NK cells (25). Interestingly, like the ER stress inducers, IFN-γ caused a dissociation of ATF6 from BiP and migration to the nucleus (Fig.…”

UPR-inducible miRNAs contribute to stressful situations

“…ER stress can modulate immune responses through regulation of MHC class I surface expression [24]. Peptides degraded by proteasome are translocated by ATP-binding cassette transporter (TAP1) into ER lumen.…”