Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions and heavy-chain misfolding
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Objective - HLA-B27 is associated with the inflammatory spondyloarthropathies (SpAs). Of significance, subtypes HLA-B*27:06 and HLA-B*27:09 are not associated with the SpAs. These subtypes primarily differ from the HLA-B*27:05 disease associated allele at residues 114 and 116 of the heavy chain, part of the F pocket of the antigen-binding groove. Dimerisation of HLA-B27 during assembly has been implicated in disease onset. This study investigated the factors influencing differences in dimerisation between disease associated and non-associated HLA-B27 alleles. Methods – HLA-B*27:05 and mutants resembling the HLA-B*27:06 and 09 subtypes were expressed in the rat C58 T cell line, the human CEM T cell line and its calnexin deficient variant CEM.NKR. Immunoprecipitation, pulse chase, flow cytometry and immunoblotting were performed to study the assembly kinetics, heavy chain dimerisation and chaperone associations. Results - By expressing HLA-B*27:05, 06-like and 09 alleles on a restrictive rat TAP peptide transporter background, we demonstrate that a tyrosine expressed at p116 or together with an aspartic acid residue at p114 inhibited HLA-B27 dimerisation and increased the assembly rate. F pocket residues alter the associations with chaperones of the early MHC class I folding pathway. Calnexin was demonstrated to participate in endoplasmic reticulum (ER) stress mediated degradation of dimers, whereas the oxidoreductase ERp57 does not appear to influence dimerization. Conclusion - Residues within the F pocket of the peptide-binding groove differing between disease-associated and non-disease-associated HLA-B27 subtypes can influence the assembly process and heavy chain dimerisation, events which have been linked to the initiation of disease pathogenesis.
Guiliano , D B , North , H , Panayoitou , E , Campbell , E C , McHugh , K , Cooke , F G M , Silvestre , M , Bowness , P , Powis , S J & Antoniou , A N 2017 , ' Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions and heavy-chain misfolding ' , Arthritis & Rheumatology , vol. 69 , no. 3 , pp. 610-621 . https://doi.org/10.1002/art.39948
Arthritis & Rheumatology
© 2016, American College of Rheumatology. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at onlinelibrary.wiley.com / https://doi.org/10.1002/art.39948
DescriptionThis work was in part funded by awards to Dr Antoniou (Arthritis Research UK Fellowship 15293) and Dr Powis (Scottish Government Chief Scientist Office ETM/56).
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