Alternative exon skipping biases substrate preference of the deubiquitylase USP15 for mysterin/RNF213, the moyamoya disease susceptibility factor.
Alternative exon skipping biases substrate preference of the deubiquitylase USP15 for mysterin/RNF213, the moyamoya disease susceptibility factor.
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DOI：
10.1038/srep44293
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发表时间：
2017-03-09
影响因子：
4.6
通讯作者：
Nagata K
中科院分区：
文献类型：
--
作者：
Kotani Y;Morito D;Sakata K;Ainuki S;Sugihara M;Hatta T;Iemura SI;Takashima S;Natsume T;Nagata K
去泛素化酶USP 15在多种细胞途径中发挥重要作用，包括TGF-β信号传导、RNA剪接和先天免疫。外显子7的进化保守跳跃发生在编码USP 15及其副产物USP 4的mRNA的转录期间，每个基因产生两种主要同种型。USP 15的外显子7编码一段富含丝氨酸的29个氨基酸残基，位于连接N端推定调控区和C端酶促区的区域间接头中。以前的研究结果表明，在接头区域的变化导致两个去泛素化酶的异构体之间的功能差异，但迄今为止，没有直接的证据，这种功能的分歧已被公布。我们发现USP 15的长亚型主要识别和去泛素化mysterin，一种与烟雾病发病相关的大型泛素连接酶。这一观察结果代表了保守的外显子跳跃改变这类去泛素化酶的底物特异性的第一个实验证据。此外，我们发现USP 15的短和长同种型的相互作用组仅部分重叠。因此，USP 15，一个在多个细胞过程中的关键基因，通过进化上保守的外显子跳跃产生两种功能不同的亚型。
The deubiquitylating enzyme USP15 plays significant roles in multiple cellular pathways including TGF-β signaling, RNA splicing, and innate immunity. Evolutionarily conserved skipping of exon 7 occurs during transcription of the mRNAs encoding USP15 and its paralogue USP4, yielding two major isoforms for each gene. Exon 7 of USP15 encodes a serine-rich stretch of 29 amino acid residues located in the inter-region linker that connects the N-terminal putative regulatory region and the C-terminal enzymatic region. Previous findings suggested that the variation in the linker region leads to functional differences between the isoforms of the two deubiquitylating enzymes, but to date no direct evidence regarding such functional divergence has been published. We found that the long isoform of USP15 predominantly recognizes and deubiquitylates mysterin, a large ubiquitin ligase associated with the onset of moyamoya disease. This observation represents the first experimental evidence that the conserved exon skipping alters the substrate specificity of this class of deubiquitylating enzymes. In addition, we found that the interactomes of the short and long isoforms of USP15 only partially overlapped. Thus, USP15, a key gene in multiple cellular processes, generates two functionally different isoforms via evolutionarily conserved exon skipping.