Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy.
Front Immunol. 2022 Sep 20;13:1002375. doi: 10.3389/fimmu.2022.1002375. eCollection 2022.
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.
内质网氨肽酶 1 和 2（ERAP1 和 ERAP2）和胰岛素调节氨肽酶（IRAP）是三种 M1 锌金属蛋白酶，其在抗原加工中的作用是在内质网（ERAP1 和 ERAP2）或内体（IRAP）中对肽谱进行精细化。然而，其他新的和独特的功能正在出现。在这里，我们特别关注 ERAP2。该基因具有特殊的进化历史，在啮齿动物中不存在，在人类中经历了两种单倍型的平衡选择，其中一种不能表达全长 ERAP2。这些观察结果表明，它在抗原呈递中的作用不是必需的。另一个较少研究的作用是调节肾素-血管紧张素系统（RAS）。ERAP1 和 ERAP2 将血管紧张素 II（Ang II）切割成 Ang III 和 IV，它们拮抗 Ang II 的作用，而 IRAP 本身就是 Ang IV 的受体。我们最近报道称，巨噬细胞独立于单倍型表达并释放一种 N 端 ERAP2“短”形式，该形式可直接结合 IRAP，并且这两种分子在内涵体和细胞膜上共表达。这一新证据表明，人类 ERAP2 基因的维持可能与其在 RAS 系统调节中的活性有关，可能作为 Ang IV 激动剂。本文讨论了其在免疫介导性疾病以及与 RAS 系统失衡相关的疾病（包括高血压、先兆子痫，但也包括 COVID-19 等病毒感染）中的作用。
