Antigen processing and presentation: Potential link to AS

Proteins destined to be degraded are ubiquitylated and broken down into peptides by the proteasome. Peptides that have an excessive number of amino acids at the N-terminal, which cannot be accommodated on class I MHC molecules, enter the ER and are further trimmed by ERAP1 and ERAP2. Peptides of appropriate length are loaded onto class I MHC molecules such as HLA-B27 to form a peptide-HLA-B27-beta-2-macroglobulin heterotrimer. This complex is then transported to the cell surface via the Golgi apparatus. Like other molecules destined to leave the ER, peptide-HLA-B27-beta-2-macroglobulin is transported through COPII vesicles. COPII vesicles are formed at a ribosome-free ER-exit site, and protein transport protein SEC16A regulates this process. Abnormal peptide complexes can form as a result of altered ERAP1 or ERAP2 activities, resulting in abnormal surface peptide-HLA-B27-beta-2-macroglobulin complexes. Unstable peptide-HLA-B27 complexes can accumulate in the ER, triggering the UPR, ERAD, and autophagy. Defects in COPII vesicle formation, ERAD, or autophagy could potentially amplify UPR responses. Furthermore, free heavy chains of misfolded HLA-B27 can combine to form dimers.