LETTER LETTER

ERAP1 biology and assessment in

We read with interest the work of Reeves preferences, form heterodimers, and work ences in the aminopeptidase pathway in mice et al. on endoplasmic reticulum amino- in concert to trim peptides. This difference and humans. Reeves et al.’s(1)conclusions peptidase 1 (ERAP1) haplotypes found in means that extrapolation of murine ER ami- are not robust because they fail to meet both Ankylosing Spondylitis (AS), and have sev- nopeptidase research to humans requires these criteria. eral concerns about the study and its con- a high degree of caution. For example, Reeves clusions (1). et al. (1) state that ERAP1-deficient cells have Philip C. Robinsona,1 and Reeves et al. (1) claim, on the basis of se- 20–30% reduction in MHC class I presenta- Matthew A. Brownb quence data from 19 cases and 17 controls, tion, citing previously published data from aCentre for Neurogenetics and Statistical that two haplotypes (*002 and *011) have ERAAP-deficient mice (2). In contrast, in Genomics, Queensland Brain Institute, reduced frequency in cases and two (*001 humans ERAP1 knockdown can reduce de- University of Queensland, Brisbane, QLD and *005) have increased frequency. Two of struction of MHC ligands and increase the 4072, Australia; and bUniversity of these four haplotypes actually have no statis- surface expression of MHC class I molecules Queensland Diamantina Institute, tically significant difference (Fisher’sexact (3), ERAP2 deficiency reduces surface MHC P values > 0.05 for *005 and *011), and class I presentation (4), and the effect of Translational Research Institute, Princess one is marginally associated (P = 0.045, hap- combined ERAP1 and ERAP2 deficiency in Alexandra Hospital, Brisbane, QLD 4102, lotype *001), and not associated if appropri- humans, analogous to ERAAP deficiency Australia ate levels of multiple comparison correction in mice, is unknown. are applied. With the exception of the studies Reeves et al. (1) conclude that ERAP1 var- 1 Reeves E, Colebatch-Bourn A, Elliott T, Edwards CJ, James E (2014) using the ERAP1 KO 293T cell line, all of the iation is involved in AS through effects on Functionally distinct ERAP1 allotype combinations distinguish findingsofthestudyarebasedonthecon- antigen trimming. However, the in vitro individuals with Ankylosing Spondylitis. Proc Natl Acad Sci USA clusion that there is differential association of model used in this study does not directly 111(49):17594–17599. 2 Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N (2006) the ERAP1 haplotypes with AS; given that assay trimming function, but rather the entire The aminopeptidase ERAAP shapes the peptide repertoire displayed that has not been demonstrated, these con- MHC class I processing and presentation by major histocompatibility complex class I molecules. Nat Immunol clusions are not robust. pathway. The observation that AS-associated 7(1):103–112. 3 York IA, et al. (2002) The ER aminopeptidase ERAP1 enhances or As Reeves et al. (1) themselves point out, ERAP1 haplotypes are associated with re- limits antigen presentation by trimming epitopes to 8-9 residues. Nat they also observe a risk association with duced MHC– complex levels can be Immunol 3(12):1177–1184. rs30187, in contrast to the findings of multi- explained by either decreased trimming to 4 Andrés AM, et al.; NISC Comparative Sequencing Program (2010) Balancing selection maintains a form of ERAP2 that undergoes ple association studies in both Asian- and produce ligands or by destruction of ligands nonsense-mediated decay and affects antigen presentation. PLoS European-descent populations. (3). In vitro models measuring trimming Genet 6(10):e1001157. Reeves et al. (1) investigate the effects of function directly show that SNPs associated 5 Evans DM, et al.; Spondyloarthritis Research Consortium of Canada (SPARCC); Australo-Anglo-American Spondyloarthritis ERAP1 variation, transfecting human ERAP1 with increased risk of AS are associated Consortium (TASC); Wellcome Trust Case Control Consortium 2 (and N-terminally extended peptide) into with increased trimming velocity of human (WTCCC2) (2011) Interaction between ERAP1 and HLA-B27 in “Erap1-deficient” murine cells. However, ERAP1 (5). ankylosing spondylitis implicates peptide handling in the mechanism Nat Genet – mice have only one identified ER resident Further studies of the role of aminopepti- for HLA-B27 in disease susceptibility. 43(8):761 767. aminopeptidase (termed “ERAAP” for ER dase variants in human disease should be aminopeptidase associated with antigen pro- based on firm data as to the direction of Author contributions: P.C.R. and M.A.B. wrote the paper. cessing, not “Erap1”), not two (ERAP1 genetic association of the variants or haplo- The authors declare no conflict of interest. and ERAP2)asinhumans.Inhumans, types studied, and if using experimental 1To whom correspondence should be addressed. Email: philip. ERAP1 and ERAP2 have different peptide animals, take into account the major differ- [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1501475112 PNAS Early Edition | 1of1 Downloaded by guest on October 3, 2021