Nuclear export of ubiquitinated proteins via the UBIN-POST system.
Nuclear export of ubiquitinated proteins via the UBIN-POST system.
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DOI：
10.1073/pnas.1711017115
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发表时间：
2018-05-01
影响因子：
11.1
通讯作者：
Nagata K
中科院分区：
文献类型：
--
作者：
Hirayama S;Sugihara M;Morito D;Iemura SI;Natsume T;Murata S;Nagata K
通常观察到，蛋白酶体损伤导致细胞质中泛素化蛋白的积累。甚至原本位于细胞核中的蛋白质也表现出类似的细胞质积累，这表明未知的机制主动将它们运输到细胞质中。在这里，我们报道了一种蛋白质复合物，ubin多泛素化底物转运体，含有泛素结合域和核输出信号特异性地介导了这一过程。此外，在自然条件下，它们的同系物具有相似的运输活性，对维持蠕虫的寿命具有重要意义。我们的发现提供了一个长期存在的问题的答案，为什么泛素化蛋白沉积在细胞质蛋白酶体损伤；它们提供了潜在的分子机制的明确鉴定，并显示了其在动物细胞中蛋白质静止的基本参与。尽管细胞质中蛋白质稳态的机制已被广泛研究，但细胞核中的机制仍不甚清楚。在这里，我们发现一种蛋白质复合物介导多泛素化蛋白从细胞核到细胞质的输出。UBIN是一种含泛素相关（UBA）结构域的蛋白，尽管缺乏内在核输出信号（NES），但仍以crm1依赖的方式在细胞核和细胞质之间穿梭。相反，UBIN结合蛋白多泛素化底物转运蛋白（POST）携带一个NES将UBIN通过核孔运送。UBIN通过其UBA结构域与多泛素链结合，UBIN- post复合物将它们从细胞核输出到细胞质中。泛素化蛋白在蛋白酶体抑制下在细胞质中积累，而与CRM1抑制剂共处理导致其在细胞核中积累。我们的研究结果表明，泛素化蛋白以UBIN-POST复合物依赖的方式从细胞核输出到细胞质，以维持核蛋白的稳态。
It is commonly observed that proteasome impairment results in accumulation of ubiquitinated proteins in the cytosol. Even proteins originally located in the nucleus show similar cytosolic accumulation, suggesting that unidentified machinery proactively transports them to the cytosol. Here, we report that a protein complex, UBIN–polyubiquitinated substrate transporter, harboring ubiquitin binding domain and nuclear export signal specifically mediates this process. In addition, their worm homologues showing similar transportation activity are important to maintain the lifespan of worms under natural condition. Our findings provide an answer to the long-standing question of why ubiquitinated proteins are deposited in the cytosol by proteasome impairment; they provide definite identification of underlying molecular machinery and show its essential involvement in the proteostasis in animal cells. Although mechanisms for protein homeostasis in the cytosol have been studied extensively, those in the nucleus remain largely unknown. Here, we identified that a protein complex mediates export of polyubiquitinated proteins from the nucleus to the cytosol. UBIN, a ubiquitin-associated (UBA) domain-containing protein, shuttled between the nucleus and the cytosol in a CRM1-dependent manner, despite the lack of intrinsic nuclear export signal (NES). Instead, the UBIN binding protein polyubiquitinated substrate transporter (POST) harboring an NES shuttled UBIN through nuclear pores. UBIN bound to polyubiquitin chain through its UBA domain, and the UBIN-POST complex exported them from the nucleus to the cytosol. Ubiquitinated proteins accumulated in the cytosol in response to proteasome inhibition, whereas cotreatment with CRM1 inhibitor led to their accumulation in the nucleus. Our results suggest that ubiquitinated proteins are exported from the nucleus to the cytosol in the UBIN-POST complex-dependent manner for the maintenance of nuclear protein homeostasis.
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DOI：
10.1016/j.bbamcr.2010.10.014
发表时间：
2011-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Chook YM;Süel KE
通讯作者：
Süel KE
影响因子：
7.2
作者：
Chen, Bryan;Retzlaff, Marco;Frydman, Judith
通讯作者：
Frydman, Judith
影响因子：
4.1
作者：
Bryantsev, Anton L.;Kurchashova, Svetlana Yu.;Kampinga, Harm H.
通讯作者：
Kampinga, Harm H.
DOI：
10.1006/bbrc.1994.2586
发表时间：
1994-11-15
影响因子：
3.1
作者：
KAMPINGA, HH;BRUNSTING, JF;LANDRY, J
通讯作者：
LANDRY, J
影响因子：
3.3
作者：
Ernoult-Lange, Michele;Wilczynska, Ania;Weil, Dominique
通讯作者：
Weil, Dominique