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The unfolded protein response and HLA-B27\ud misfolding: implications for ankylosing\ud spondylitis



The unfolded protein response (UPR) detects the presence of misfolded proteins in\ud the endoplasmic reticulum (ER) and subsequently relieves ER stress by increasing\ud the folding capacity of the ER. The secretory pathway substrate HLA-B27 is highly\ud associated with the chronic inflammatory disease ankylosing spondylitis (AS) and\ud has a tendency to misfold in the ER. Here, we show that overexpression of HLA-B27\ud and non-disease associated HLA-B7 in immortalised cell lines leads to heavy chain\ud misoxidation, which is accompanied by upregulation of BiP and splicing of XBP1, a\ud key step in the IRE1 pathway of the UPR which is increasingly being linked with\ud intestinal inflammation.\ud We also demonstrate that different cell lines respond to different ER stress stimuli in\ud distinct ways. We establish that HT1080 cells inefficiently induce a UPR in response\ud to tunicamycin and that this has consequences for cell survival. However, inefficient\ud activation of the UPR in HT1080 cells can be overcome by secondary signals, since\ud co-administration of the tyrosine kinase inhibitor genistein leads to activation of\ud XBP1. Furthermore, we show that genistein can inhibit UPR induction of BiP in\ud response to a range of ER stresses indicating that the cancer drug genistein can\ud inhibit or activate the UPR depending on the environment and cell type. This has\ud implications for inflammatory disease since regulation of the UPR is important in\ud determining a cell’s tendency towards apoptosis

Topics: HLA-B27, protein misfolding, UPR, unfolded protein response, ankylosing spondylitis
Year: 2010
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Provided by: Durham e-Theses

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