An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding
An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding
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DOI：
10.1074/jbc.m300456200
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发表时间：
2003-08-01
影响因子：
4.8
通讯作者：
Levine, SJ
中科院分区：
文献类型：
--
作者：
Cui, XL;Rouhani, FN;Levine, SJ
TNFR 1脱落的氨肽酶调节剂（ARTS-1）与I型肿瘤坏死因子受体（TNFR 1）结合并促进受体脱落。由于基于异羟肟酸的金属蛋白酶抑制剂阻止TNFR 1和白细胞介素-6受体（IL-6 R α）的脱落，我们假设ARTS-1也可能调节IL-6 R α的脱落，IL-6 R α是I型细胞因子受体超家族的成员，在结构上不同于TNFR 1。相互免疫共沉淀实验鉴定了膜相关ARTS-1直接结合55-kDa IL-6 R α，其大小与通过膜结合受体的胞外域切割产生的可溶性IL-6 R α一致。此外，ARTS-1促进IL-6 R α脱落，如在过表达ARTS-1的细胞系中增加的膜相关ARTS-1蛋白、增加的IL-6 R α脱落和减少的膜相关IL-6 R α之间的直接相关性所证明的。arts-1敲除细胞不存在基础IL-6 R α脱落，这表明ARTS-1是组成性IL-6 R α脱落所必需的。此外，组成性IL-6 Ra脱落的机制需要ARTS-1催化活性。因此，ARTS-1促进两种细胞因子受体超家族的脱落，即I型细胞因子受体超家族（IL-6 R α）和TNF受体超家族（TNFR 1）。我们认为，ARTS-1是一种多功能氨肽酶，可能通过促进IL-6 R α和TNFR 1脱落来调节炎症事件。
Aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the type I tumor necrosis factor receptor (TNFR1) and promotes receptor shedding. Because hydroxamic acid-based metalloprotease inhibitors prevent shedding of both TNFR1 and the interleukin-6 receptor (IL-6Ralpha), we hypothesized that ARTS-1 might also regulate shedding of IL-6Ralpha, a member of the type I cytokine receptor superfamily that is structurally different from TNFR1. Reciprocal co-immunoprecipitation experiments identified that membrane-associated ARTS-1 directly binds to a 55-kDa IL-6Ralpha, a size consistent with soluble IL-6Ralpha generated by ectodomain cleavage of the membrane-bound receptor. Furthermore, ARTS-1 promoted IL-6Ralpha shedding, as demonstrated by a direct correlation between increased membrane-associated ARTS-1 protein, increased IL-6Ralpha shedding, and decreased membrane-associated IL-6Ralpha in cell lines overexpressing ARTS-1. The absence of basal IL-6Ralpha shedding from arts-1 knock-out cells identified that ARTS-1 was required for constitutive IL-6Ralpha shedding. Furthermore, the mechanism of constitutive IL-6Ralpha shedding requires ARTS-1 catalytic activity. Thus, ARTS-1 promotes the shedding of two cytokine receptor superfamilies, the type I cytokine receptor superfamily (IL-6Ralpha) and the TNF receptor superfamily (TNFR1). We propose that ARTS-1 is a multifunctional aminopeptidase that may modulate inflammatory events by promoting IL-6Ralpha and TNFR1 shedding.