Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes?
Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes?
复制标题
为什么与 K63-多聚泛素链连接的细胞蛋白不与蛋白酶体结合？
DOI：
10.1038/emboj.2012.354
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发表时间：
2013-02-20
期刊：
影响因子：
11.4
通讯作者：
Goldberg, Alfred L.
中科院分区：
文献类型：
--
作者：
Nathan, James A.;Kim, Hyoung Tae;Ting, Lily;Gygi, Steven P.;Goldberg, Alfred L.
虽然与K48连接的Ub链结合的细胞蛋白是以蛋白酶体为靶标的，但与K63-泛素链结合的蛋白质是针对溶酶体的。然而，纯26S蛋白酶体类似地结合和降解K48-和K63-泛素化底物。因此，我们研究了为什么K63泛素化的蛋白不被蛋白酶体降解。我们发现哺乳动物细胞含有选择性地与K63链结合的可溶性因子，并抑制或阻止它们与蛋白酶体的联系。以泛素化的蛋白质作为亲和配基，我们发现与K63链选择性结合并阻断其与蛋白酶体结合的主要细胞蛋白是ESCRT0及其组分STAM和HRS。在体内，ESCRT0基因的敲除证实了它是阻断K63泛素化分子与蛋白酶体结合所必需的。此外，RAD23蛋白，特别是hHR23B，被发现能与K48泛素化蛋白特异性结合，并刺激蛋白酶体结合。K48-或K63-泛素链的这些蛋白质的特异性决定了泛素化的蛋白质是作为蛋白酶体降解的靶标，还是转送到内体-溶酶体途径。
Although cellular proteins conjugated to K48-linked Ub chains are targeted to proteasomes, proteins conjugated to K63-ubiquitin chains are directed to lysosomes. However, pure 26S proteasomes bind and degrade K48- and K63-ubiquitinated substrates similarly. Therefore, we investigated why K63-ubiquitinated proteins are not degraded by proteasomes. We show that mammalian cells contain soluble factors that selectively bind to K63-chains and inhibit or prevent their association with proteasomes. Using ubiquitinated proteins as affinity ligands, we found that the main cellular proteins that associate selectively with K63-chains and block their binding to proteasomes are ESCRT0 and its components, STAM and Hrs. In vivo, knockdown of ESCRT0 confirmed that it is required to block binding of K63-ubiquitinated molecules to the proteasome. In addition, the Rad23 proteins, especially hHR23B, were found to bind specifically to K48-ubiquitinated proteins and to stimulate proteasome binding. The specificities of these proteins for K48- or K63-ubiquitin chains determine whether a ubiquitinated protein is targeted for proteasomal degradation or delivered instead to the endosomal-lysosomal pathway.
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