Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP.
Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP.
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DOI：
10.1371/journal.pone.0006868
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发表时间：
2009-08-31
期刊：
影响因子：
3.7
通讯作者：
Lee AS
中科院分区：
文献类型：
--
作者：
Ni M;Zhou H;Wey S;Baumeister P;Lee AS
未折叠蛋白反应（UPR）是一种进化上保守的机制，允许细胞适应针对内质网（ER）的应激。诱导内质网伴侣蛋白GRP78/BiP增加蛋白折叠能力；因此，它是普遍定期审议的一个主要生存环节。考虑到普遍定期审议在调节细胞生存和死亡中的核心重要性，越来越多的证据表明细胞进化出反馈调节途径来调节关键的普遍定期审议执行者，然而，确切的机制仍有待阐明。在这里，我们报告了GRP78va的偶然发现，GRP78va是GRP78的一种新的异构体，由可变剪接（内含子1的保留）和可变翻译起始产生。生物信息学和生化分析显示，GRP78va的表达在内质网应激下增强，在人白血病细胞和白血病患者中显著升高。典型的GRP78主要是内质网管蛋白，而GRP78va缺乏内质网信号肽，是细胞质性的。通过siRNA特异性敲低内源性GRP78va而不影响标准GRP78，我们发现GRP78va促进内质网应激下的细胞存活。我们进一步证明GRP78va具有调节PERK信号的能力，并且GRP78va能够与PERK抑制剂P58IPK相互作用并拮抗。我们的研究描述了GRP78/BiP的一种新的细胞质异构体GRP78va的发现，并首次表征了通过核前mrna的选择性剪接来调节UPR信号。我们的研究进一步揭示了在白血病细胞和其他表达GRP78va的细胞类型中的一种新的存活机制。
The unfolded protein response (UPR) is an evolutionarily conserved mechanism to allow cells to adapt to stress targeting the endoplasmic reticulum (ER). Induction of ER chaperone GRP78/BiP increases protein folding capacity; as such it represents a major survival arm of UPR. Considering the central importance of the UPR in regulating cell survival and death, evidence is emerging that cells evolve feedback regulatory pathways to modulate the key UPR executors, however, the precise mechanisms remain to be elucidated. Here, we report the fortuitous discovery of GRP78va, a novel isoform of GRP78 generated by alternative splicing (retention of intron 1) and alternative translation initiation. Bioinformatic and biochemical analyses revealed that expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. In contrast to the canonical GRP78 which is primarily an ER lumenal protein, GRP78va is devoid of the ER signaling peptide and is cytosolic. Through specific knockdown of endogenous GRP78va by siRNA without affecting canonical GRP78, we showed that GRP78va promotes cell survival under ER stress. We further demonstrated that GRP78va has the ability to regulate PERK signaling and that GRP78va is able to interact with and antagonize PERK inhibitor P58IPK. Our study describes the discovery of GRP78va, a novel cytosolic isoform of GRP78/BiP, and the first characterization of the modulation of UPR signaling via alternative splicing of nuclear pre-mRNA. Our study further reveals a novel survival mechanism in leukemic cells and other cell types where GRP78va is expressed.
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影响因子：
11.2
作者：
Fu, Yong;Li, Jianze;Lee, Amy S.
通讯作者：
Lee, Amy S.
影响因子：
4.8
作者：
Khan, MM;Nomura, T;Ishii, S
通讯作者：
Ishii, S
DOI：
10.1073/pnas.0807691105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Fu, Yong;Wey, Shiuan;Lee, Amy S.
通讯作者：
Lee, Amy S.
影响因子：
4.8
作者：
Lee, AS
通讯作者：
Lee, AS
DOI：
10.1083/jcb.106.4.1093
发表时间：
1988-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Garcia PD;Ou JH;Rutter WJ;Walter P
通讯作者：
Walter P