Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network.
Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network.
复制标题
前蛋白转化酶弗林蛋白酶与反式高尔基体网络中的前 ADAMTS4 (Aggrecanase-1) 相互作用并裂解。
DOI：
10.1074/jbc.m312797200
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Pei,Duanqing
中科院分区：
文献类型：
--
作者：
Wang,Ping;Tortorella,Micky;England,Kristen;Malfait,Anne-Marie;Thomas,Gary;Arner,ElizabethC;Pei,Duanqing
具有血小板反应蛋白1型基序的A去整合素和金属蛋白酶结构域（ADAMTS-4）蛋白酶家族的成员可以在骨关节炎患者的关节中检测到的几个位点有效地切割聚集蛋白聚糖。虽然最近的研究表明，ADAMTS 4的前结构域的去除是其降解聚集蛋白聚糖的能力的关键，其加工和运输的细胞机制仍然不清楚。在本研究中，我们通过使用弗林蛋白酶特异性抑制剂和RNA干扰技术，证明弗林蛋白酶在ADAMTS 4前结构域的细胞内去除中起着重要作用。此外，我们证明proADAMTS 4可以通过多个弗林蛋白酶识别位点：206 RPRR 209，209 RAKR 212或211 KR 212进行处理。proADAMTS 4的加工被Brefeldin A完全阻断，表明加工发生在trans-Golgi网络中。事实上，ADAMTS 4与弗林蛋白酶共定位于高尔基体网络中。有趣的是，ADAMTS-4的前体形式，而不是其成熟形式，与弗林蛋白酶共沉淀，表明弗林蛋白酶与ADAMTS-4的前结构域物理相互作用。此外，我们的证据表明，弗林蛋白酶非依赖性途径也可能有助于ADAMTS 4的激活。这些结果表明，ADAMTS 4的激活机制可以靶向针对该酶的治疗干预。
A member of the A disintegrin and metalloproteinase domain with thrombospondin type-1 motifs (ADAMTS-4) protease family can efficiently cleave aggrecan at several sites detected in joints of osteoarthritic patients. Although recent studies have shown that removal of the prodomain of ADAMTS4 is critical for its ability to degrade aggrecan, the cellular mechanisms for its processing and trafficking remain unclear. In this study, by using both furin-specific inhibitor and RNA interference technique, we demonstrate that furin plays an important role in the intracellular removal of ADAMTS4 prodomain. Further, we demonstrate that proADAMTS4 can be processed by means of multiple furin recognition sites:206RPRR209,209RAKR212, or211KR212. The processing of proADAMTS4 was completely blocked by brefeldin A treatment, suggesting that processing occurs in thetrans-Golgi network. Indeed, ADAMTS4 is co-localized with furin intrans-Golgi network. Interestingly, the pro form of ADAMTS4, not its mature one, co-precipitates with furin, suggesting that furin physically interacts with the prodomain of ADAMTS-4. In addition, our evidence suggests that a furin-independent pathway may also contribute to the activation of ADAMTS4. These results indicate that the activation mechanism for ADAMTS4 can be targeted for therapeutical intervention against this enzyme.