A splice acceptor variant in HLA‐DRA affects the conformation and cellular localization of the class II DR alpha‐chain. Issue 2 (19th October 2020)

• Record Type: Journal Article
• Authors: Didonna, Alessandro; Damotte, Vincent; Shams, Hengameh; Matsunaga, Atsuko; Caillier, Stacy J.; Dandekar, Ravi; Misra, Maneesh K.; Mofrad, Mohammad R. K.; Oksenberg, Jorge R.; Hollenbach, Jill A.
• Is Part Of: Immunology. Volume 162:Issue 2(2021)
• Page Start: 194
• Page End: 207
• Publication Date: 2020-10-19
• Subjects: antigen presentation -- human leucocyte antigen -- immune response -- protein folding; Immunology -- Periodicals
• DOI: 10.1111/imm.13273
• Languages: English
• ISSNs: 0019-2805

Abstract

Summary: Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen‐derived peptides to CD4 + T lymphocytes. At the molecular level, they are constituted by α/β‐heterodimers on the surface of professional antigen‐presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA ‐ DRA gene mediates the transcription of an alternative version of the α‐chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA‐DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding β‐chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide‐binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA‐DRA functions as a novel intact antigen for class II HLA molecules. Abstract : The acceptor variant (rs8084) in the HLA‐DRA gene mediates the transcription of an alternative version of the alpha‐chain lacking 25 amino acids in its extracellular domain. This short isoform functions as a novel intact antigen for canonical class II HLA molecules.