The emerging multifunctional roles of ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation

Abstract

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 “short” 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.

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“…This hypothesis was validated in vitro a few months later [ 132 ] and, at present, we hypothesize further that ANG II upregulation is also caused by deficient endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2), which break down ANG II into ANG III and ANG IV ( Figure 3 ). In addition, others have shown that ANG II disrupts IL-7Rs, enabling viral thriving by inducing immune senescence [ 133 ].…”

“…The ER harbors ERAP1 and ERAP2, zinc-metalloproteases, which have been implicated in CVD and PTSD (via OXT depletion) [ 133 , 163 , 164 ]. Indeed, ERAP2 functions as an oxytocinase, breaking down OXN and terminating its action, suggesting that a dysfunction of this enzyme may predispose it to PTSD [ 133 ].…”

“…The ER harbors ERAP1 and ERAP2, zinc-metalloproteases, which have been implicated in CVD and PTSD (via OXT depletion) [ 133 , 163 , 164 ]. Indeed, ERAP2 functions as an oxytocinase, breaking down OXN and terminating its action, suggesting that a dysfunction of this enzyme may predispose it to PTSD [ 133 ]. OXT is a prosocial hormone with cardio and neuroprotective properties, which under pathological circumstances, was associated with fibromyalgia, PTSD, and CVD [ 97 , 165 , 166 , 167 ].…”

“…Several studies have reported that ERAP1 and ERAP2 hydrolyze ANG II into ANG III and ANG IV, contributing to the rapid clearance of this toxic peptide ( Figure 3 ). Interestingly, ERAP2 maintains two haplotypes, a long and a short one, of which the latter can be decayed, accounting for approximately 25% of the population which does not express this protein [ 133 ].…”

“…Interestingly, a new study has reported that ERAP2 likely decreased the vulnerability to Yersinia pestis during the Middle Ages epidemic in Europe, the Middle East, and Northern Africa, emphasizing the antimicrobial properties of this protein [ 178 ]. The same authors surmise that ERAP2 resilience to plague may have contributed to the development of modern diseases, including autoimmunity [ 133 , 179 , 180 ]. We surmise that ERAP2 protects against PTSD and CVD and that loss of this protein drives thymus-mediated autoimmunity, predisposing to these pathologies [ 181 , 182 ].…”