Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Science. 2012 Jan 13;335(6065):225-8. doi: 10.1126/science.1214400.
The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFα-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the endoplasmic reticulum. The failure of TACE to exit the endoplasmic reticulum in the absence of iRhom2 prevents the furin-mediated maturation and trafficking of TACE to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target.
细胞因子肿瘤坏死因子（TNF）是炎症的主要触发因素。像许多细胞外信号蛋白一样，TNF 最初被合成成为一种跨膜蛋白；其活性信号是它的细胞外结构域，在 ADAM 家族金属蛋白酶 ADAM17（TNFα 转化酶，TACE）切割后从细胞中脱落。我们报告称，rhomboid 家族中无蛋白水解活性的成员 iRhom2 是小鼠中 TNF 释放所必需的。iRhom2 与 TACE 结合并促进其从内质网中输出。如果没有 iRhom2，TACE 无法从内质网中输出，这会阻止 furin 介导的 TACE 成熟以及将其运输到细胞表面，也就是 TNF 切割的部位。鉴于 TNF 在自身免疫和炎症性疾病中的作用，iRhom2 可能代表一个有吸引力的治疗靶点。
