Protein ligands to HuR modulate its interaction with target mRNAs in vivo.
Protein ligands to HuR modulate its interaction with target mRNAs in vivo.
复制标题
蛋白配体用于HUR调节其与体内靶标mRNA的相互作用。
DOI：
10.1083/jcb.151.1.1
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发表时间：
2000-10-02
影响因子：
7.8
通讯作者：
Steitz, J A
中科院分区：
文献类型：
--
作者：
Brennan, C M;Gallouzi, I E;Steitz, J A
富au元素（AREs）存在于许多原癌基因、细胞因子和淋巴因子信息的3 '非翻译区，可靶向它们进行快速降解。HuR是一种普遍表达的ELAV（胚胎致死性异常视觉）RNA结合蛋白家族成员，在瞬时转染的细胞中选择性地结合AREs并稳定含有AREs的mrna。在这里，我们确定了四种结合HuR区域的哺乳动物蛋白，这些蛋白对其在细胞核和细胞质之间穿梭以及稳定mRNA的能力至关重要：SETα， SETβ， pp32和富含亮氨酸的酸性蛋白（APRIL）。据报道有三种是蛋白磷酸酶2A抑制剂。所有四种配体都含有长而酸性的cooh末端尾部，而pp32和APRIL具有第二个基序：在它们的nh2末端区域具有类似rev的富含亮氨酸的重复序列。我们发现pp32和APRIL是核细胞质穿梭蛋白，可与核输出因子CRM1（染色体区域维持蛋白1）相互作用。leptomycin B对CRM1的抑制导致pp32和APRIL的核保留，它们与HuR的关联增加，以及HuR与核poly(A)+ RNA的关联增加。此外，含有are的c-fos基因的转录本选择性地保留在细胞核中，而总poly(A)+ RNA的细胞质分布不会改变。这些数据提供了证据，证明其配体与HuR的相互作用调节了HuR在体内结合其靶mrna的能力，并表明CRM1在某些条件下至少有助于一些细胞mrna的输出。我们讨论了HuR上游这些配体在控制含are mrna稳定性的途径中的可能作用。
AU-rich elements (AREs) present in the 3′ untranslated regions of many protooncogene, cytokine, and lymphokine messages target them for rapid degradation. HuR, a ubiquitously expressed member of the ELAV (embryonic lethal abnormal vision) family of RNA binding proteins, selectively binds AREs and stabilizes ARE-containing mRNAs in transiently transfected cells. Here, we identify four mammalian proteins that bind regions of HuR known to be essential for its ability to shuttle between the nucleus and the cytoplasm and to stabilize mRNA: SETα, SETβ, pp32, and acidic protein rich in leucine (APRIL). Three have been reported to be protein phosphatase 2A inhibitors. All four ligands contain long, acidic COOH-terminal tails, while pp32 and APRIL share a second motif: rev-like leucine-rich repeats in their NH2-terminal regions. We show that pp32 and APRIL are nucleocytoplasmic shuttling proteins that interact with the nuclear export factor CRM1 (chromosomal region maintenance protein 1). The inhibition of CRM1 by leptomycin B leads to the nuclear retention of pp32 and APRIL, their increased association with HuR, and an increase in HuR's association with nuclear poly(A)+ RNA. Furthermore, transcripts from the ARE-containing c-fos gene are selectively retained in the nucleus, while the cytoplasmic distribution of total poly(A)+ RNA is not altered. These data provide evidence that interaction of its ligands with HuR modulate HuR's ability to bind its target mRNAs in vivo and suggest that CRM1 is instrumental in the export of at least some cellular mRNAs under certain conditions. We discuss the possible role of these ligands upstream of HuR in pathways that govern the stability of ARE-containing mRNAs.