pXBP1(U), a negative regulator of the unfolded protein response activator pXBP1(S), targets ATF6 but not ATF4 in proteasome-mediated degradation.
pXBP1(U), a negative regulator of the unfolded protein response activator pXBP1(S), targets ATF6 but not ATF4 in proteasome-mediated degradation.
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DOI：
10.1247/csf.06028
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发表时间：
2009
影响因子：
1.5
通讯作者：
H. Yoshida;A. Uemura;K. Mori
中科院分区：
文献类型：
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作者：
H. Yoshida;A. Uemura;K. Mori
当未折叠的蛋白质在内质网（ER）应激条件下在ER中积累时，从酵母到人类的细胞激活非常规mRNA剪接。哺乳动物细胞中这种剪接的底物是XBP 1 mRNA，其编码未折叠蛋白反应（UPR）特异性转录因子XBP 1。由于剪接，XBP 1的C-末端区域被转换。因此，未剪接和剪接的mRNA分别产生261 aa的pXBP 1（U）和376 aa的pXBP 1（S），其中含有共享的DNA结合结构域的N-末端区域。由于pXBP 1（S）特异性C-末端区域作为激活结构域起作用，因此pXBP 1（S）可以有效地激活转录。我们最近发现，由于在pXBP 1（U）特异性C-末端区域存在核排斥信号，pXBP 1（U）在细胞核和细胞质之间穿梭，这与pXBP 1（S）的专门核定位形成鲜明对比。pXBP 1（U）与pXBP 1（S）结合，pXBP 1（U）-pXBP 1（S）复合物被蛋白酶体迅速降解。另外两种转录因子在ER应激时被激活，即ATF 6和ATF 4。ATF 6是UPR特异性转录因子，而ATF 4不仅被ER应激激活，而且被各种其他刺激激活。在这项研究中，我们发现pXBP 1（U）靶向活性形式的ATF 6，而不是ATF 4，通过直接关联被蛋白酶体破坏。这种增强的降解由位于pXBP 1（U）特异性C末端的降解结构域介导。我们的结论是，pXBP 1（U）作为UPR特异性转录因子ATF 6和pXBP 1（S）的负调控因子。
Cells from yeast to humans activate unconventional mRNA splicing when unfolded proteins accumulate in the endoplasmic reticulum (ER) under ER stress conditions. The substrate of this splicing in mammalian cells is XBP1 mRNA, which encodes the unfolded protein response (UPR)-specific transcription factor XBP1. The C-terminal region of XBP1 is switched as a result of the splicing. Thus, unspliced and spliced mRNAs produce pXBP1(U) of 261 aa and pXBP1(S) of 376 aa, respectively, with the N-terminal region containing the DNA-binding domain shared. As the pXBP1(S)-specific C-terminal region functions as an activation domain, pXBP1(S) can activate transcription efficiently. We recently found that pXBP1(U) shuttles between the nucleus and cytoplasm, owing to the presence of a nuclear exclusion signal in the pXBP1(U)-specific C-terminal region, in marked contrast to the exclusively nuclear localization of pXBP1(S). pXBP1(U) can associate with pXBP1(S), and pXBP1(U)-pXBP1(S) complex is rapidly degraded by the proteasome. Two other transcription factors are activated in response to ER stress, namely ATF6 and ATF4. ATF6 is a UPR-specific transcription factor, whereas ATF4 is activated by not only ER stress but also various other stimuli. In this study, we show that pXBP1(U) targets the active form of ATF6 but not ATF4 for destruction by the proteasome via direct association. This enhanced degradation is mediated by the degradation domain located at the pXBP1(U)-specific C-terminal end. We conclude that pXBP1(U) functions as a negative regulator of the UPR-specific transcription factors ATF6 and pXBP1(S).