The Prolyl Isomerase Pin1 Targets Stem-Loop Binding Protein (SLBP) To Dissociate the SLBP-Histone mRNA Complex Linking Histone mRNA Decay with SLBP Ubiquitination
The Prolyl Isomerase Pin1 Targets Stem-Loop Binding Protein (SLBP) To Dissociate the SLBP-Histone mRNA Complex Linking Histone mRNA Decay with SLBP Ubiquitination
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DOI：
10.1128/mcb.00382-12
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发表时间：
2012-11-01
影响因子：
5.3
通讯作者：
Thapar, Roopa
中科院分区：
文献类型：
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作者：
Krishnan, Nithya;Lam, TuKiet T.;Thapar, Roopa
组蛋白mRNA在S期结束时迅速降解，并且3'非翻译区中的26个核苷酸的茎环是组蛋白mRNA稳定性的关键决定因素。该序列是茎环结合蛋白（SLBP）的结合位点，其有助于将RNA降解机制的组分募集到组蛋白mRNA的3'端。SLBP是唯一的蛋白质，其表达在S期期间受到细胞周期调节，并且其降解与组蛋白mRNA降解在时间上相关。在这里，我们报告说，化学抑制脯氨酰异构酶Pin 1或下调Pin 1的小干扰RNA（siRNA）增加了所有五个核心组蛋白mRNA的mRNA稳定性和SLBP的稳定性。Pin 1通过N端的Ser 20/Ser 23磷酸降解决定子调节SLBP的多聚泛素化。Pin 1的siRNA敲低导致SLBP在细胞核中积累。我们发现，Pin 1可以沿着与蛋白磷酸酶2A（PP 2A）在体外脱磷酸化的磷酸苏氨酸在一个保守的TPNK序列中的SLBP RNA结合域，从而解离SLBP从组蛋白mRNA发夹。我们的数据表明，Pin 1和PP 2A的行为协调SLBP的降解泛素蛋白酶体系统和外泌体介导的降解组蛋白mRNA通过调节复合物解离。
Histone mRNAs are rapidly degraded at the end of S phase, and a 26-nucleotide stem-loop in the 3' untranslated region is a key determinant of histone mRNA stability. This sequence is the binding site for stem-loop binding protein (SLBP), which helps to recruit components of the RNA degradation machinery to the histone mRNA 3' end. SLBP is the only protein whose expression is cell cycle regulated during S phase and whose degradation is temporally correlated with histone mRNA degradation. Here we report that chemical inhibition of the prolyl isomerase Pin1 or downregulation of Pin1 by small interfering RNA (siRNA) increases the mRNA stability of all five core histone mRNAs and the stability of SLBP. Pin1 regulates SLBP polyubiquitination via the Ser20/Ser23 phosphodegron in the N terminus. siRNA knockdown of Pin1 results in accumulation of SLBP in the nucleus. We show that Pin1 can act along with protein phosphatase 2A (PP2A) in vitro to dephosphorylate a phosphothreonine in a conserved TPNK sequence in the SLBP RNA binding domain, thereby dissociating SLBP from the histone mRNA hairpin. Our data suggest that Pin1 and PP2A act to coordinate the degradation of SLBP by the ubiquitin proteasome system and the exosome-mediated degradation of the histone mRNA by regulating complex dissociation.