A Short ERAP2 That Binds IRAP Is Expressed in Macrophages Independently of Gene Variation

Abstract

The M1 zinc metalloproteases ERAP1, ERAP2, and IRAP play a role in HLA-I antigen presentation by refining the peptidome either in the ER (ERAP1 and ERAP2) or in the endosomes (IRAP). They have also been entrusted with other, although less defined, functions such as the regulation of the angiotensin system and blood pressure. In humans, ERAP1 and IRAP are commonly expressed. ERAP2 instead has evolved under balancing selection that maintains two haplotypes, one of which undergoing RNA splicing leading to nonsense-mediated decay and loss of protein. Hence, likewise in rodents, wherein the ERAP2 gene is missing, about a quarter of the human population does not express ERAP2. We report here that macrophages, but not monocytes or other mononuclear blood cells, express and secrete an ERAP2 shorter form independent of the haplotype. The generation of this “short” ERAP2 is due to an autocatalytic cleavage within a distinctive structural motif and requires an acidic micro-environment. Remarkably, ERAP2 “short” binds IRAP and the two molecules are co-expressed in the endosomes as well as in the cell membrane. Of note, the same phenomenon could be observed in some cancer cells. These data prompt us to reconsider the role of ERAP2, which might have been maintained in humans due to fulfilling a relevant function in its “short” form.

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

“…A less efficient cleavage of Ang II by the ERAPs, due to polymorphic variations, could lead to an imbalance of the RAS system in favor of an inflammatory state, NO production inhibition and hypertension, atherosclerosis and vasoconstriction ( Figure 1 ). A new form of ERAP2, that is expressed and secreted regardless of gene variations by M2 macrophages, but not by monocytes or other blood mononuclear cells, has been recently described by our group ( 25 ). This “short” form, most likely generated by an autocatalytic process in the endosomes, has a molecular weight of about 55 KDa and maintains the ERAP2 N-terminal end.…”

“…It must be pointed out that this is different from the ERAP2/iso3 variant of similar MW, an alternative spliced isoform described as triggered by flu-infection and other pathogens including HIV (Human Immunodeficiency Virus), SARS-CoV-2, CMV (Cytomegalovirus) and LPS-positive bacteria and which, however, does not possess enzymatic activity per se (58,59). Most interestingly, the "short" ERAP2 directly binds IRAP and it is co-expressed in endosomes as well as on the cell membrane (25). This is a novel finding that connects for the first time the two aminopeptidases, ERAP2 and IRAP, which can eventually co-operate in the RAS system, although at this stage Schematic representation of the Renin-Angiotensin System (RAS).…”

“…There are, however, exceptions. For instance some transformed cells, although being genotyped as G/G at rs2248374, have been shown to express full length ERAP2 ( 24 , 25 ), suggesting that the NMD can be overcome under some circumstances. Interestingly, an ortholog of the ERAP2 gene is lacking in several other species among which rodents ( 6 ).…”

Macrophage Polarization: Learning to Manage It

“…Remarkably, Mattorre and colleagues, for the first time, reported the existence of a short form of aminopeptidase ERAP2 secreted exclusively by macrophages of the M2subtype in all individuals regardless of the haplotype expressing the full-length form of ERAP2 [7]. It should be noted that the binding of ERAP2 to IRAP (called oxytocinase) can interfere with the renin-angiotensin system (RAS) by inhibiting its anti-inflammatory properties, and thus contributing to many pathologies ranging from autoimmune and inflammatory diseases, hypertension and cancer to SARS-CoV-2 [7] (Figure 2C).…”

“…(B) Mechanical vibration induced an intermediate Mφ phenotype in fracture healing[6]. (C) ERAP2 short form caused an inhibition of anti-inflammatory ativity of Renin Angiotensin System[7]. (D)Anti-tumor ativity is increased with the addition of adjuvant M. obuense[8].…”