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Immunol."],"abstract":"<jats:p>The Endoplasmic Reticulum Aminopeptidase 1 and 2 (ERAP1 and ERAP2) and Insulin Regulated Aminopeptidase (IRAP) are three M1 zinc metalloproteases whose role in antigen processing is the refining of peptidome either in the Endoplasmic reticulum (ERAP1 and ERAP2), or in the endosomes (IRAP). However, other novel and distinct functions are emerging. Here, we focus specifically on ERAP2. This gene has a peculiar evolutionary history, being absent in rodents and undergoing in humans to a balanced selection of two haplotypes, one of which not expressing the full length ERAP2. These observations suggest that its role in antigen presentation is not essential. An additional, less investigated role is in the regulation of the Renin Angiotensin System (RAS). ERAP1 and ERAP2 cleave Angiotensin II (Ang II) into Ang III and IV, which counteract the action of Ang II whereas IRAP is itself the receptor for Ang IV. We have recently reported that macrophages, independently from the haplotype, express and release a N-terminus ERAP2 \u201cshort\u201d form which directly binds IRAP and the two molecules are co-expressed in the endosomes and on the cell membrane. This new evidence suggests that the maintenance of the ERAP2 gene in humans could be due to its activity in the regulation of the RAS system, possibly as an Ang IV agonist. Its role in the immune-mediated diseases as well as in disorders more specifically related to an imbalance of the RAS system, including hypertension, pre-eclampsia but also viral infections such as COVID-19, is discussed here.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1002375","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T09:51:38Z","timestamp":1663667498000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["The emerging multifunctional roles of\u00a0ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation"],"prefix":"10.3389","volume":"13","author":[{"given":"Benedetta","family":"Mattorre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Tedeschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Paldino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Fiorillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Paladini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr987","article-title":"MEROPS: the database of proteolytic enzymes, their substrates and inhibitors","volume":"40","author":"Rawlings","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1208","article-title":"Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum","volume":"6","author":"Saveanu","year":"2005","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/ni860","article-title":"The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8\u20139 residues","volume":"3","author":"York","year":"2002","journal-title":"Nat Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.685909","article-title":"Structural basis for antigenic peptide recognition and processing by endoplasmic reticulum (ER) aminopeptidase 2","volume":"290","author":"Mpakali","year":"2015","journal-title":"J Biol Chem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001157","article-title":"Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation","volume":"6","author":"Andr\u00e9s","year":"2010","journal-title":"PLoS Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01576","article-title":"The multifaceted nature of aminopeptidases ERAP1, ERAP2, and LNPEP: From evolution to disease","volume":"11","author":"Paladini","year":"2020","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1172845","article-title":"IRAP identifies an endosomal compartment required for MHC class I cross-presentation","volume":"325","author":"Saveanu","year":"2009","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.molimm.2016.08.005","article-title":"Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-i-associated inflammatory disorders: towards a unifying view","volume":"77","author":"L\u00f3pez de Castro","year":"2016","journal-title":"Mol Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249608","article-title":"The impact of the 'Mis-peptidome' on HLA class I-mediated diseases: Contribution of ERAP1 and ERAP2 and effects on the immune response","volume":"21","author":"Tedeschi","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B10","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrrheum.2015.133","article-title":"Genetics of ankylosing spondylitis - 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