Abstract
The Endoplasmic reticulum aminopeptidase I (ERAP1) trims peptides to their optimal size for binding to Major Histocompatibility Complex class I proteins. The natural polymorphism of this enzyme is associated with ankylosing spondylitis (AS) in epistasis with the major risk factor for this disease, HLA-B*27, suggesting a direct relationship between AS and HLA-B*27-bound peptides. Three polymorphisms that affect peptide trimming protect from AS: K528R, D575N/R725Q, and Q730E. We characterized and ranked the effects of each mutation, and their various combinations, by quantitative comparisons of the HLA-B*27 peptidomes from cells expressing distinct ERAP1 variants. Five features were examined: peptide length, N-terminal flanking residues, N-terminal residues of the natural ligands, internal sequences and affinity for B*27:05. Polymorphism at residue 528 showed the largest influence, affecting all five features regardless of peptide length. D575N/R725Q showed a much smaller effect. Yet, when co-occurring with K528R, it further decreased ERAP1 activity. Polymorphism at residue 730 showed a significant influence on peptide length, because of distinct effects on trimming of nonamers compared with longer peptides. Accordingly, multiple features were affected by the Q730E mutation in a length-dependent way. The alterations induced in the B*27:05 peptidome by natural ERAP1 variants with different K528R/Q730E combinations reflected separate and additive effects of both mutations. Thus, the influence of ERAP1 on HLA-B*27 is very diverse at the population level, because of the multiplicity and complexity of ERAP1 variants, and to the distinct effects of their co-occurring polymorphisms, leading to significant modulation of disease risk among HLA-B*27-positive individuals.
Highlights
ERAP1 is a polymorphic aminopeptidase of the endoplasmic reticulum expressed in all individuals, whose best characterized function is to trim peptides to their proper length for Major Histocompatibility Complex Class I (MHC-I)1 molecules [1, 2]
The IRϾ1.5 subset included those peptides showing higher expression differences in each cell line compared with the other. This classification is based on our previous studies showing that ERAP1/ERAP2-dependent differences in MHC-I peptidomes are best revealed among peptides in the IRϾ1.5 subset and are usually attenuated or absent altogether in the IRϾ1.0 –1.5 group. This is expected from the fact that quantitative effects of ERAP1 polymorphism on MHC-I ligands should be mainly observed among peptides showing larger differences in relative amounts between the cell lines compared
ERAP1, ERAP2, and HLA-B*27 Expression in HLA-B*27:05 Positive Cell Lines— the expression of ERAP1 and ERAP2 in the four cell lines used in this study were separately assessed in previous reports [26, 35], their relative protein levels were jointly determined by Western blotting in the context of the present study (Fig. 1A–1B)
Summary
ERAP1 is a polymorphic aminopeptidase of the endoplasmic reticulum expressed in all individuals, whose best characterized function is to trim peptides to their proper length for Major Histocompatibility Complex Class I (MHC-I)1 molecules [1, 2]. By selecting cell lines with ERAP1 variants showing different combinations of polymorphic residues, we could assign distinct effects to individual disease-associated changes, rank their relative contribution to shaping the HLAB*27 peptidome, and define the interactive effects among cooccurring polymorphisms in the natural ERAP1 haplotypes.
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