Ubiquitin ligase activity inhibits Cdk5 to control axon termination.
Ubiquitin ligase activity inhibits Cdk5 to control axon termination.
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泛素连接酶活性抑制CDK5以控制轴突终止。
DOI：
10.1371/journal.pgen.1010152
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发表时间：
2022-04
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
Cdk 5激酶在神经系统发育、可塑性、行为和疾病中起着重要作用。它在癌症、免疫系统和胰岛素分泌中也具有重要的非神经元功能。目前，我们还不完全了解限制Cdk 5的负调控机制。在这里，我们使用秀丽隐杆线虫显示，CDK-5被RPM-1/FSN-1泛素连接酶复合物抑制。这种非典型RING泛素连接酶是C.通过哺乳动物的进化。我们的发现源于无偏倚的体内亲和纯化蛋白质组学，该蛋白质组学将CDK-5鉴定为推定的RPM-1底物。基于CRISPR的天然生物化学显示，CDK-5与RPM-1/FSN-1泛素连接酶复合物相互作用。CRISPR工程化RPM-1底物“陷阱”富集CDK-5结合，其由FSN-1底物识别模块介导。为了测试RPM-1/FSN-1泛素连接酶复合物和CDK-5之间的功能遗传关系，我们评估了机械感觉神经元和运动神经元中的轴突终止。我们的研究结果表明RPM-1/FSN-1泛素连接酶活性限制CDK-5控制轴突终止。总的来说，这些蛋白质组学、生物化学和遗传学结果增加了我们对神经系统中抑制Cdk 5的机制的理解。Cdk 5是一种非典型的细胞周期蛋白依赖性激酶，在神经系统发育、可塑性和疾病中发挥重要作用。几十年的研究都集中在了解Cdk 5是如何被激活的。相比之下，我们对限制Cdk 5活性的遗传和分子机制知之甚少。在这里，我们研究了如何Cdk 5在神经系统中被抑制使用模式生物C。优雅我们的结果表明RPM-1/FSN-1 E3泛素连接酶复合物抑制Cdk 5来控制轴突生长的终止。我们的发现是，遍在蛋白连接酶活性在体内限制神经系统中的Cdk 5，这开辟了一种有趣的可能性，即遍在蛋白连接酶活性可能在其他细胞环境和疾病环境中调节Cdk 5。
The Cdk5 kinase plays prominent roles in nervous system development, plasticity, behavior and disease. It also has important, non-neuronal functions in cancer, the immune system and insulin secretion. At present, we do not fully understand negative regulatory mechanisms that restrict Cdk5. Here, we use Caenorhabditis elegans to show that CDK-5 is inhibited by the RPM-1/FSN-1 ubiquitin ligase complex. This atypical RING ubiquitin ligase is conserved from C. elegans through mammals. Our finding originated from unbiased, in vivo affinity purification proteomics, which identified CDK-5 as a putative RPM-1 substrate. CRISPR-based, native biochemistry showed that CDK-5 interacts with the RPM-1/FSN-1 ubiquitin ligase complex. A CRISPR engineered RPM-1 substrate ‘trap’ enriched CDK-5 binding, which was mediated by the FSN-1 substrate recognition module. To test the functional genetic relationship between the RPM-1/FSN-1 ubiquitin ligase complex and CDK-5, we evaluated axon termination in mechanosensory neurons and motor neurons. Our results indicate that RPM-1/FSN-1 ubiquitin ligase activity restricts CDK-5 to control axon termination. Collectively, these proteomic, biochemical and genetic results increase our understanding of mechanisms that restrain Cdk5 in the nervous system. Cdk5 is an atypical cyclin dependent kinase and an important player in nervous system development, plasticity, and disease. Decades of research has focused on understanding how Cdk5 is activated. In contrast, we know much less about the genetic and molecular mechanisms that restrict Cdk5 activity. Here, we examined how Cdk5 is inhibited in the nervous system using the model organism C. elegans. Our results indicate that the RPM-1/FSN-1 E3 ubiquitin ligase complex inhibits Cdk5 to control termination of axon growth. Our finding that ubiquitin ligase activity restricts Cdk5 in the nervous system in vivo now opens up the interesting possibility that ubiquitin ligase activity might regulate Cdk5 in other cellular contexts and disease settings.
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DOI：
10.1038/s41583-020-0269-3
发表时间：
2020-04
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Coleman MP;Höke A
通讯作者：
Höke A
影响因子：
4.8
作者：
Desbois, Muriel;Crawley, Oliver;Grill, Brock
通讯作者：
Grill, Brock
影响因子：
64.8
作者：
Harris JA;Mihalas S;Hirokawa KE;Whitesell JD;Choi H;Bernard A;Bohn P;Caldejon S;Casal L;Cho A;Feiner A;Feng D;Gaudreault N;Gerfen CR;Graddis N;Groblewski PA;Henry AM;Ho A;Howard R;Knox JE;Kuan L;Kuang X;Lecoq J;Lesnar P;Li Y;Luviano J;McConoughey S;Mortrud MT;Naeemi M;Ng L;Oh SW;Ouellette B;Shen E;Sorensen SA;Wakeman W;Wang Q;Wang Y;Williford A;Phillips JW;Jones AR;Koch C;Zeng H
通讯作者：
Zeng H
影响因子：
16.6
作者：
Crawley, Oliver;Opperman, Karla J.;Grill, Brock
通讯作者：
Grill, Brock
影响因子：
9.2
作者：
Connell-Crowley, L;Le Gall, M;Giniger, E
通讯作者：
Giniger, E