Activation of the unfolded protein response and alternative splicing of ATF6alpha in HLA-B27 positive lymphocytes.

Misfolding of major histocompatibility complex (MHC) class I molecules has been implicated in the rheumatic autoimmune disease ankylosing spondylitis (AS), and has been linked to the unfolded protein response (UPR) in rodent AS models. XBP1 and ATF6alpha are two important transcription factors that initiate and co-ordinate the UPR. Here we show that misoxidised MHC class I heavy chains activate XBP1 processing in a similar manner to tunicamycin, with tunicamycin and dithiothreitol (DTT) inducing differential XBP1 processing. Unexpectedly, ATF6alpha mRNA is alternatively spliced during reducing stress in lymphocytes. This shorter ATF6alpha message lacks exon 7 and may have a regulatory role in the UPR.