Evnouchidou Irini, Kamal Ram P, Seregin Sergey S, Goto Yoshikuni, Tsujimoto Masafumi, Hattori Akira, Voulgari Paraskevi V, Drosos Alexandros A, Amalfitano Andrea, York Ian A, Stratikos Efstratios
Protein Chemistry Laboratory, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece.
J Immunol. 2011 Feb 15;186(4):1909-13. doi: 10.4049/jimmunol.1003337. Epub 2011 Jan 17.
ER aminopeptidase 1 (ERAP1) customizes antigenic peptide precursors for MHC class I presentation and edits the antigenic peptide repertoire. Coding single nucleotide polymorphisms (SNPs) in ERAP1 were recently linked with predisposition to autoimmune disease, suggesting a link between pathogenesis of autoimmunity and ERAP1-mediated Ag processing. To investigate this possibility, we analyzed the effect that disease-linked SNPs have on Ag processing by ERAP1 in vitro. Michaelis-Menten analysis revealed that the presence of SNPs affects the Michaelis constant and turnover number of the enzyme. Strikingly, specific ERAP1 allele-substrate combinations deviate from standard Michaelis-Menten behavior, demonstrating substrate-inhibition kinetics; to our knowledge, this phenomenon has not been described for this enzyme. Cell-based Ag-presentation analysis was consistent with changes in the substrate inhibition constant K(i), further supporting that ERAP1 allelic composition may affect Ag processing in vivo. We propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity.
内质网氨肽酶1（ERAP1）为MHC I类呈递定制抗原肽前体，并编辑抗原肽库。ERAP1中的编码单核苷酸多态性（SNP）最近与自身免疫性疾病的易感性相关，提示自身免疫发病机制与ERAP1介导的抗原加工之间存在联系。为了研究这种可能性，我们在体外分析了疾病相关SNP对ERAP1抗原加工的影响。米氏分析表明，SNP的存在会影响该酶的米氏常数和周转数。引人注目的是，特定的ERAP1等位基因-底物组合偏离了标准的米氏行为，表现出底物抑制动力学；据我们所知，这种现象尚未在该酶中被描述。基于细胞的抗原呈递分析与底物抑制常数K（i）的变化一致，进一步支持ERAP1等位基因组成可能影响体内抗原加工。我们建议在评估抗原加工与自身免疫之间的可能联系时应考虑这些现象。
