Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Int J Mol Sci. 2022 Apr 29;23(9):4961. doi: 10.3390/ijms23094961.
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.
M1 锌金属蛋白酶 ERAP1、ERAP2 和 IRAP 通过在 ER（ERAP1 和 ERAP2）或内体中细化肽组来发挥 HLA-I 抗原呈递的作用。它们还承担了其他一些功能，尽管这些功能不太明确，如调节血管紧张素系统和血压。在人类中，通常表达 ERAP1 和 IRAP。而 ERAP2 则经历了平衡选择的进化，这种选择维持了两种单倍型，其中一种单倍型发生 RNA 剪接，导致无意义介导的衰变和蛋白质丢失。因此，在啮齿动物中，由于 ERAP2 基因缺失，大约四分之一的人类不表达 ERAP2。我们在这里报告，巨噬细胞，但不是单核细胞或其他单核血细胞，表达和分泌一种不依赖于单倍型的 ERAP2 较短形式。这种“短”ERAP2 的产生是由于在独特的结构基序内发生自催化裂解，并且需要酸性微环境。值得注意的是，ERAP2“短”形式与 IRAP 结合，这两种分子在内涵体和细胞膜上共同表达。值得注意的是，在一些癌细胞中也可以观察到同样的现象。这些数据促使我们重新考虑 ERAP2 的作用，由于其“短”形式具有相关功能，因此在人类中得以维持。
