Membrane Traffic Lab, Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal.
Membrane Traffic Lab, Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Oeiras, Portugal.
Cell Rep. 2017 Oct 17;21(3):745-757. doi: 10.1016/j.celrep.2017.09.074.
Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.
细胞表面金属蛋白酶在发育、组织稳态和疾病中协调信号转导。TACE（肿瘤坏死因子-α转换酶）负责切割（“脱落”）膜结合的信号分子，包括细胞因子 TNF 和 EGFR 的激活配体。TACE 在分泌途径中的运输需要与其结合 iRhom2，这介导了 TACE 从内质网的输出。TACE 生物学的一个重要但机制尚不清楚的特征是，它能够被许多炎症和促进生长的因子在细胞表面迅速刺激。在这里，我们报告了 iRhom2 在细胞表面 TACE 刺激中的作用。TACE 脱落刺激物触发 MAP 激酶依赖性磷酸化 iRhom2 N 端细胞质尾巴。这招募了 14-3-3 蛋白，强制 TACE 与 iRhom2 复合物解离，促进 TACE 底物的切割。我们的数据表明，iRhom2 控制着 TACE 生物学的多个方面，包括细胞表面的刺激性脱落。
