Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, Iowa, USA.
J Leukoc Biol. 2019 Oct;106(4):823-835. doi: 10.1002/JLB.3VMR0219-069R. Epub 2019 Aug 1.
iRhoms are related to a family of intramembrane serine proteinases called rhomboids but lack proteolytic activity. In mammals, there are two iRhoms, iRhom1 and iRhom2, which have similar domain structures and overlapping specificities as well as distinctive functions. These catalytically inactive rhomboids are essential regulators for the maturation and trafficking of the disintegrin metalloprotease ADAM17 from the endoplasmic reticulum to the cell surface, and are required for the cleavage and release of a variety of membrane-associated proteins, including the IL-6 receptor, l-selectin, TNF, and EGFR ligands. iRhom2-dependent regulation of ADAM17 function has been recently implicated in the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy. In this review, we discuss our current understanding of iRhom biology, their implications in autoimmune pathologies, and their potential as therapeutic targets.
iRhoms 与一类称为 rhomboids 的跨膜丝氨酸蛋白酶家族有关，但缺乏蛋白水解活性。在哺乳动物中，有两种 iRhoms，即 iRhom1 和 iRhom2，它们具有相似的结构域结构和重叠的特异性以及独特的功能。这些无催化活性的 rhomboids 是调节跨膜金属蛋白酶 ADAM17 从内质网到细胞表面成熟和运输的重要调节剂，并且是多种膜相关蛋白（包括 IL-6 受体、l-选择素、TNF 和 EGFR 配体）的切割和释放所必需的。最近的研究表明，iRhom2 依赖性调节 ADAM17 功能与几种自身免疫性疾病的发展和进展有关，包括类风湿关节炎、狼疮肾炎以及血友病性关节炎。在这篇综述中，我们讨论了我们对 iRhoms 生物学的理解、它们在自身免疫病理学中的意义以及它们作为治疗靶点的潜力。
