iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling.

iRhoms 是类菱形超家族的假蛋白酶成员，是炎症和生长因子信号传导的主要调节因子；它们主要通过识别客户的跨膜域来发挥作用。在这里，我们报告了 iRhoms 机制上不同的核功能，表明人和小鼠 iRhom2 都是信号肽酶复合物 (SPC) 的非典型底物，信号肽酶复合物是一种从分泌蛋白中去除信号肽的蛋白酶。 iRhom2 的裂解产生 N 端片段，该片段进入细胞核并部分通过结合 C 端结合蛋白 (CtBP) 来修改转录组。银屑病、食管癌 (TOC) 和非表皮松解性掌跖角化病 (NEPPK) 患者皮肤活检中 iRhom2 水平升高表明了核 iRhom2 的生物学意义；银屑病角质形成细胞模型中 iRhom2 裂解增加；核iRhom2促进角​​质形成细胞增殖。总体而言，这项工作确定了一种意想不到的 SPC 依赖性 ER 至细胞核信号传导途径，并证明 iRhoms 可以介导核信号传导。