pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response.
pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response.
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DOI：
10.1083/jcb.200508145
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发表时间：
2006-02-13
期刊：
影响因子：
--
通讯作者：
Mori K
中科院分区：
文献类型：
--
作者：
Yoshida H;Oku M;Suzuki M;Mori K
在哺乳动物内质网（ER）中积累未折叠蛋白后，X-box结合蛋白1（XBP 1）前信使RNA（premRNA）通过由核酸内切酶肌醇需要酶1介导的非常规剪接转化为成熟mRNA。转录因子蛋白（p）XBP 1剪接（S）由成熟的XBP 1 mRNA翻译而来，含有核定位信号和转录激活结构域，并激活靶基因的转录，包括那些在核中编码ER分子伴侣的基因。我们发现，编码在XBP 1前mRNA中的pXBP 1未剪接（U）在ER应激的恢复期组成性表达并显著积累。pXBP 1（U）含有核排斥信号而不是转录激活结构域，穿梭于细胞核和细胞质之间。有趣的是，pXBP 1（U）与pXBP 1（S）形成复合物，并且pXBP 1（U）-pXBP 1（S）复合物从核中隔离。此外，由于pXBP 1（U）中含有降解基序，该复合物被蛋白酶体快速降解。因此，pXBP 1（U）是pXBP 1（S）的负反馈调节剂，其在ER应激的恢复阶段关闭靶基因的转录。
Upon the accumulation of unfolded proteins in the mammalian endoplasmic reticulum (ER), X-box binding protein 1 (XBP1) premessenger RNA (premRNA) is converted to mature mRNA by unconventional splicing that is mediated by the endonuclease inositol-requiring enzyme 1. The transcription factor protein (p) XBP1 spliced (S), which is translated from mature XBP1 mRNA, contains the nuclear localization signal and the transcriptional activation domain and activates the transcription of target genes, including those encoding ER chaperones in the nucleus. We show that pXBP1 unspliced (U) encoded in XBP1 pre-mRNA was constitutively expressed and markedly accumulated at the recovery phase of ER stress. pXBP1(U) contained the nuclear exclusion signal instead of the transcriptional activation domain and shuttled between the nucleus and the cytoplasm. Interestingly, pXBP1(U) formed a complex with pXBP1(S), and the pXBP1(U)–pXBP1(S) complex was sequestered from the nucleus. Moreover, the complex was rapidly degraded by proteasomes because of the degradation motif contained in pXBP1(U). Thus, pXBP1(U) is a negative feedback regulator of pXBP1(S), which shuts off the transcription of target genes during the recovery phase of ER stress.
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