So Byung Ran, Wan Lili, Zhang Zhenxi, Li Pilong, Babiash Eric, Duan Jingqi, Younis Ihab, Dreyfuss Gideon
Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Nat Struct Mol Biol. 2016 Mar;23(3):225-30. doi: 10.1038/nsmb.3167. Epub 2016 Feb 1.
Despite equal snRNP stoichiometry in spliceosomes, U1 snRNP (U1) is typically the most abundant vertebrate snRNP. Mechanisms regulating U1 overabundance and snRNP repertoire are unknown. In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins. We show that the human U1-specific RBP U1-70K can bridge pre-U1 to SMN-Gemin2-Sm, in a Gemin5-independent manner, thus establishing an additional and U1-exclusive Sm core-assembly pathway. U1-70K hijacks SMN-Gemin2-Sm, enhancing Sm-core assembly on U1s and inhibiting that on other snRNAs, thereby promoting U1 overabundance and regulating snRNP repertoire. SMN-Gemin2's ability to facilitate transactions between different RBPs and RNAs explains its multi-RBP valency and the myriad transcriptome perturbations associated with SMN deficiency in neurodegenerative spinal muscular atrophy. We propose that SMN-Gemin2 is a versatile hub for RNP exchange that functions broadly in RNA metabolism.
尽管剪接体中的小核核糖核蛋白（snRNP）化学计量相等，但U1小核核糖核蛋白（U1）通常是脊椎动物中最丰富的snRNP。调节U1过量和snRNP组成的机制尚不清楚。在Sm核心组装过程中，由SMN复合体介导的一个关键的snRNP生物合成步骤，snRNA特异性RNA结合蛋白（RBP）Gemin5传递前体snRNA，这些前体snRNA与SMN-Gemin2招募的Sm蛋白结合。我们发现，人类U1特异性RBP U1-70K可以以不依赖Gemin5的方式将前体U1与SMN-Gemin2-Sm连接起来，从而建立了一条额外的、U1特有的Sm核心组装途径。U1-70K劫持SMN-Gemin2-Sm，增强U1上的Sm核心组装并抑制其他snRNA上的组装，从而促进U1过量并调节snRNP组成。SMN-Gemin2促进不同RBP和RNA之间相互作用的能力解释了其多RBP价态以及与神经退行性脊髓性肌萎缩症中SMN缺陷相关的无数转录组扰动。我们提出，SMN-Gemin2是一个多功能的RNP交换中心，在RNA代谢中广泛发挥作用。
