Proteolytic Cleavage Governs Interleukin-11 Trans-signaling
Proteolytic Cleavage Governs Interleukin-11 Trans-signaling
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DOI：
10.1016/j.celrep.2016.01.053
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发表时间：
2016-02-23
期刊：
影响因子：
8.8
通讯作者：
Garbers, Christoph
中科院分区：
文献类型：
--
作者：
Lokau, Juliane;Nitz, Rebecca;Garbers, Christoph
白介素11已被证明是肠道肿瘤发生、肺癌和哮喘的关键因素。IL-11被认为是通过膜结合的IL-11受体(IL-11R)的细胞类型特异性表达来唯一地介导其生物学功能。在这里，我们证明了金属蛋白酶ADAM10，而不是ADAM17，可以释放IL-11R胞外结构域。IL-11R和IL-6受体(IL-6R)的嵌合蛋白表明，ADAM17的这种底物特异性是由一小部分膜旁引起的。此外，我们还发现丝氨酸蛋白酶、中性粒细胞弹性蛋白酶和蛋白酶3也能裂解IL-11R。由此产生的可溶性IL-11R(sIL-11R)具有生物活性，并与IL-11结合以激活细胞。这种IL-11转导信号通路可以被抗炎治疗化合物sgp130Fc特异性地抑制。总之，IL-11R的蛋白分解代表着一个分子开关，它控制着IL-11转导信号通路，并扩大了可被IL-11激活的细胞数量。
Interleukin (IL)-11 has been shown to be a crucial factor for intestinal tumorigenesis, lung carcinomas, and asthma. IL-11 is thought to exclusively mediate its biological functions through cell-type-specific expression of the membrane-bound IL-11 receptor (IL-11R). Here, we show that the metalloprotease ADAM10, but not ADAM17, can release the IL-11R ectodomain. Chimeric proteins of the IL-11R and the IL-6 receptor (IL-6R) revealed that a small juxtamembrane portion is responsible for this substrate specificity of ADAM17. Furthermore, we show that the serine proteases neutrophil elastase and proteinase 3 can also cleave the IL-11R. The resulting soluble IL-11R (sIL-11R) is biologically active and binds IL-11 to activate cells. This IL-11 trans-signaling pathway can be inhibited specifically by the antiinflammatory therapeutic compound sgp130Fc. In conclusion, proteolysis of the IL-11R represents a molecular switch that controls the IL-11 transsignaling pathway and widens the number of cells that can be activated by IL-11.