Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling.
Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling.
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DOI：
10.1016/j.devcel.2020.09.025
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发表时间：
2020-12-07
影响因子：
11.8
通讯作者：
Findlay GM
中科院分区：
文献类型：
--
作者：
Bustos F;Segarra-Fas A;Nardocci G;Cassidy A;Antico O;Davidson L;Brandenburg L;Macartney TJ;Toth R;Hastie CJ;Moran J;Gourlay R;Varghese J;Soares RF;Montecino M;Findlay GM
在后生动物进化过程中，具有核心细胞功能的保守蛋白激酶经常被重新部署，以调节专门的发育过程。富含丝氨酸/精氨酸（SR）的剪接因子（SRSF）蛋白激酶（SRPK）参与剪接调节，是这样一种保守的真核激酶。令人惊讶的是，我们发现SRPK已经获得了控制神经发育泛素信号通路的能力。在哺乳动物胚胎干细胞和培养的神经元中，SRPK磷酸化RNF 12/RLIM中的Ser-Arg基序，RNF 12/RLIM是一种关键的发育E3泛素连接酶，在智力残疾综合征中突变。SRPK的过程性磷酸化刺激核转录因子底物的RNF 12依赖性泛素化，从而抑制在智力残疾中异常表达的神经基因表达程序。SRPK家族基因也在智力残疾障碍中突变，并且患者来源的SRPK点突变损害RNF 12磷酸化。我们的数据揭示了SRPK调节泛素信号传导的功能多样化，以确保神经发育基因表达的正确调节。SRPK已经获得了调节RNF 12的发育功能，通过SRPK促进E3连接酶活性和核锚定SRPK-RNF 12信号传导至REX 1转录因子控制神经基因。显示SRPK剪接因子激酶已获得发育功能-磷酸化RNF 12 E3泛素连接酶以促进转录因子REX 1降解。该信号通路调节神经发育基因表达程序，并在神经发育障碍患者中发生突变。
Conserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. The Ser/Arg (SR)-rich splicing factor (SRSF) protein kinase (SRPK), which is implicated in splicing regulation, is one such conserved eukaryotic kinase. Surprisingly, we show that SRPK has acquired the capacity to control a neurodevelopmental ubiquitin signaling pathway. In mammalian embryonic stem cells and cultured neurons, SRPK phosphorylates Ser-Arg motifs in RNF12/RLIM, a key developmental E3 ubiquitin ligase that is mutated in an intellectual disability syndrome. Processive phosphorylation by SRPK stimulates RNF12-dependent ubiquitylation of nuclear transcription factor substrates, thereby acting to restrain a neural gene expression program that is aberrantly expressed in intellectual disability. SRPK family genes are also mutated in intellectual disability disorders, and patient-derived SRPK point mutations impair RNF12 phosphorylation. Our data reveal unappreciated functional diversification of SRPK to regulate ubiquitin signaling that ensures correct regulation of neurodevelopmental gene expression. SRPK has acquired a developmental function regulating RNF12 RNF12 phosphorylation by SRPK promotes E3 ligase activity and nuclear anchoring SRPK-RNF12 signaling to the REX1 transcription factor controls neural genes This signaling network is disrupted in neurodevelopmental disorders Bustos et al. show that SRPK splicing factor kinase has acquired a developmental function— phosphorylating the RNF12 E3 ubiquitin ligase to promote degradation of the transcription factor, REX1. This signaling pathway regulates a neurodevelopmental gene expression program and is mutated in patients with neurodevelopmental disorders.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
2.7
作者：
Coles, EG;Gammill, LS;Bronner-Fraser, M
通讯作者：
Bronner-Fraser, M
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影响因子：
3.7
作者：
Chen Q;Wang H;Schwender H;Zhang T;Hetmanski JB;Chou YH;Ye X;Yeow V;Chong SS;Zhang B;Jabs EW;Parker MM;Scott AF;Beaty TH
通讯作者：
Beaty TH
影响因子：
21.3
作者：
Cohen, P
通讯作者：
Cohen, P
影响因子：
7.7
作者：
Fernandez-Alonso R;Davidson L;Hukelmann J;Zengerle M;Prescott AR;Lamond A;Ciulli A;Sapkota GP;Findlay GM
通讯作者：
Findlay GM