Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K
Apoptosis-linked changes in the phosphorylation status and subcellular localization of the spliceosomal autoantigen U1-70K
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DOI：
10.1038/sj.cdd.4402312
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发表时间：
2008-04-01
影响因子：
12.4
通讯作者：
Muller, S.
中科院分区：
文献类型：
--
作者：
Dieker, J.;Cisterna, B.;Muller, S.
细胞凋亡由高度调控的途径组成，涉及翻译后修饰和蛋白质裂解，导致主要细胞过程连续失活。在这里，我们重点关注 mRNA 剪接机制的重要组成部分之一 U1-70K snRNP 蛋白的凋亡加工。我们发现，在细胞凋亡的早期阶段，在 caspase-3 切割蛋白质的 C 端部分之前，位于 RNA 识别基序内的 Ser140 残基的基础磷酸化非常显着增加。 U1-70K 蛋白的子集中发生半胱天冬酶依赖性、PP1 介导的其他丝氨酸残基去磷酸化。 Ser140 处磷酸化的 U1-70K 蛋白聚集在异质异位 RNP 衍生结构中，最终在凋亡小体中被挤出。我们鉴定出的剪接体 U1-70K 蛋白的精细加工可能在早期细胞凋亡过程中 mRNA 剪接机制的调节破坏中发挥重要作用。此外，U1-70K 蛋白的磷酸化/去磷酸化平衡和亚细胞定位的这些特定变化可能解释了为什么包含 Ser140 残基的区域成为自身免疫性疾病系统性红斑狼疮期间的中心自身抗原。
Apoptosis consists of highly regulated pathways involving post-translational modifications and cleavage of proteins leading to sequential inactivation of the main cellular processes. Here, we focused on the apoptotic processing of one of the essential components of the mRNA splicing machinery, the U1-70K snRNP protein. We found that at an early stage of apoptosis, before the cleavage of the C-terminal part of the protein by caspase-3, the basal phosphorylation of the Ser140 residue located within the RNA recognition motif, increases very significantly. A caspase-dependent, PP1-mediated dephosphorylation of other serine residues takes place in a subset of U1-70K proteins. The U1-70K protein phosphorylated at Ser140 is clustered in heterogeneous ectopic RNP-derived structures, which are finally extruded in apoptotic bodies. The elaborate processing of the spliceosomal U1-70K protein we identified might play an important role in the regulated breakdown of the mRNA splicing machinery during early apoptosis. In addition, these specific changes in the phosphorylation/dephosphorylation balance and the subcellular localization of the U1-70K protein might explain why the region encompassing the Ser140 residue becomes a central autoantigen during the autoimmune disease systemic lupus erythematosus.