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Durham e-Theses
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The unfolded protein response and HLA-B27
misfolding: implications for ankylosing

LEMIN, ANDREW,JAMES (2010) The unfolded protein response and HLA-B27
misfolding: implications for ankylosing
Doctoral thesis, Durham University.

PDF - Accepted Version


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

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:HLA-B27; protein misfolding; UPR; unfolded protein response; ankylosing spondylitis
Faculty and Department:Faculty of Science > Biological and Biomedical Sciences, School of
Thesis Date:2010
Copyright:Copyright of this thesis is held by the author
Deposited On:20 May 2011 11:51

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