DPP9 is a novel component of the N-end rule pathway targeting the tyrosine kinase Syk
DPP9 is a novel component of the N-end rule pathway targeting the tyrosine kinase Syk
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DOI：
10.7554/elife.16370
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发表时间：
2016-09-10
期刊：
影响因子：
7.7
通讯作者：
Geiss-Friedlander, Ruth
中科院分区：
文献类型：
--
作者：
Justa-Schuch, Daniela;Silva-Garcia, Maria;Geiss-Friedlander, Ruth
氨基肽酶DPP9从第二位置有脯氨酸或丙氨酸的底物的n端去除二肽。尽管与包括细胞存活和代谢在内的几种途径有关，但这些结果的分子机制尚不清楚。我们发现了DPP9与丝蛋白a的一种新的相互作用，它将DPP9招募到Syk， Syk是b细胞信号传导的一种中心激酶。Syk信号可以通过降解终止，需要泛素E3连接酶Cbl。我们发现DPP9分裂Syk产生一个新的n端，丝氨酸位于1号位置。脉冲追踪结合诱变研究表明，Seri强烈影响Syk的稳定性。此外，DPP9沉默减少了Cbl与Syk的相互作用，这表明DPP9加工是Syk泛素化的先决条件。一致地，DPP9抑制稳定Syk，从而调节Syk信号。综上所述，我们证明了DPP9是Syk的负调节因子，并得出结论，DPP9是n端规则通路的一种新的完整氨基肽酶。
The aminopeptidase DPP9 removes dipeptides from N-termini of substrates having a proline or alanine in second position. Although linked to several pathways including cell survival and metabolism, the molecular mechanisms underlying these outcomes are poorly understood. We identified a novel interaction of DPP9 with Filamin A, which recruits DPP9 to Syk, a central kinase in B-cell signalling. Syk signalling can be terminated by degradation, requiring the ubiquitin E3 ligase Cbl. We show that DPP9 cleaves Syk to produce a neo N-terminus with serine in position 1. Pulse chases combined with mutagenesis studies reveal that Seri strongly influences Syk stability. Furthermore, DPP9 silencing reduces Cbl interaction with Syk, suggesting that DPP9 processing is a prerequisite for Syk ubiquitination. Consistently, DPP9 inhibition stabilizes Syk, thereby modulating Syk signalling. Taken together, we demonstrate DPP9 as a negative regulator of Syk and conclude that DPP9 is a novel integral aminopeptidase of the N-end rule pathway.