Abstract：
Furin primarily localizes to the trans-Golgi network (TGN), where it cleaves and activates a broad range of immature proproteins that play critical roles in cellular homeostasis, disease progression, and infection. Furin is retrieved from endosomes to the TGN after being phosphorylated, but it is still unclear how furin exits the TGN to initiate the post-Golgi trafficking and how its activity is regulated in the TGN. Here three membrane-associated RING-CH finger (MARCHF) proteins (2, 8, 9) are identified as furin E3 ubiquitin ligases, which catalyze furin K33-polyubiquitination. Polyubiquitination prevents furin from maturation by blocking its ectodomain cleavage inside cells but promotes its egress from the TGN and shedding. Further ubiquitin-specific protease 32 (USP32) is identified as the furin deubiquitinase in the TGN that counteracts the MARCHF inhibitory activity on furin. Thus, the furin post-Golgi trafficking is regulated by an interplay between polyubiquitination and phosphorylation. Polyubiquitination is required for furin anterograde transport but inhibits its proprotein convertase activity, and phosphorylation is required for furin retrograde transport to produce fully active furin inside cells.
摘要：
Furin主要位于跨高尔基网络（TGN），它切割并激活在细胞稳态中起关键作用的各种未成熟的前蛋白，疾病进展,和感染。弗林蛋白酶被磷酸化后从内体回收到TGN，但目前尚不清楚furin如何退出TGN以启动后高尔基体贩运，以及其活动在TGN中如何受到监管。在这里，三种膜相关的RING-CH指（MARCHF）蛋白（2，8，9）被鉴定为弗林蛋白酶E3泛素连接酶，催化弗林蛋白酶K33-聚泛素化。聚泛素化通过阻断其在细胞内的胞外域裂解来防止弗林蛋白酶成熟，但促进其从TGN的外出和脱落。进一步的泛素特异性蛋白酶32(USP32)被鉴定为TGN中的弗林蛋白酶去泛素化酶,其抵消对弗林蛋白酶的MARCHF抑制活性。因此，高尔基体后弗林蛋白酶的运输受到多泛素化和磷酸化之间相互作用的调节。多泛素化是furin顺行转运所必需的，但抑制其前蛋白转化酶活性，和磷酸化是弗林蛋白酶逆行运输所必需的，以在细胞内产生完全活跃的弗林蛋白酶。
