A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development.
A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development.
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DOI：
10.1038/s41467-023-40223-y
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发表时间：
2023-07-26
影响因子：
16.6
通讯作者：
Werner, Achim
中科院分区：
文献类型：
--
作者：
Asmar, Anthony J.;Abrams, Shaun R.;Hsin, Jenny;Collins, Jason C.;Yazejian, Rita M.;Wu, Youmei;Cho, Jean;Doyle, Andrew D.;Cinthala, Samhitha;Simon, Marleen;van Jaarsveld, Richard H.;Beck, David B.;Kerosuo, Laura;Werner, Achim
协调胚胎外胚层形成空间上不同的谱系以形成神经系统、表皮和神经嵴衍生的颅面结构的分子机制尚不清楚。在这里，生化疾病变异分析揭示了一个翻译后途径，驱动早期外胚层分化的脊椎动物头部。前部表达的泛素连接酶CRL 3-KLHL 4限制遍在细胞骨架调节因子CDC 42的信号传导。这种调节依赖于CDC 42激活复合物GIT 1-βPIX，CRL 3-KLHL 4利用该复合物作为底物特异性共适配体来识别和单泛素化PAK 1。令人惊讶的是，我们发现泛素化将典型的CDC 42效应器PAK 1转化为CDC 42抑制剂。CRL 3-KLHL 4或疾病相关KLHL 4变体的缺失减少PAK 1泛素化，导致CDC 42信号过度激活和外胚层图案化和神经形成缺陷。因此，基于泛素的效应子-抑制子对CDC 42信号传导的组织特异性限制对于早期面部、大脑和皮肤形成至关重要，揭示了细胞命运和形态学变化如何协调以确保器官发育。确保早期面部、大脑和皮肤形成的分子机制尚不清楚。在这里，作者揭示了一个翻译后途径，控制细胞骨架信号电路，以协调外胚层图案和神经形成。
The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and neural crest-derived craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. This regulation relies on the CDC42-activating complex GIT1-βPIX, which CRL3-KLHL4 exploits as a substrate-specific co-adaptor to recognize and monoubiquitylate PAK1. Surprisingly, we find that ubiquitylation converts the canonical CDC42 effector PAK1 into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific restriction of CDC42 signaling by a ubiquitin-based effector-to-inhibitor is essential for early face, brain, and skin formation, revealing how cell-fate and morphometric changes are coordinated to ensure faithful organ development. The molecular mechanisms ensuring early face, brain, and skin formation are unclear. Here, the authors uncover a posttranslational pathway that controls cytoskeletal signaling circuits to coordinate ectodermal patterning and neurulation.
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DOI：
10.1161/hypertensionaha.121.17624
发表时间：
2022-01
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Chatrathi HE;Collins JC;Wolfe LA;Markello TC;Adams DR;Gahl WA;Werner A;Sharma P
通讯作者：
Sharma P
影响因子：
16
作者：
Akopian D;McGourty CA;Rapé M
通讯作者：
Rapé M
DOI：
10.1007/978-1-0716-0623-0_10
发表时间：
2020-01-01
期刊：
IN SITU HYBRIDIZATION PROTOCOLS, 5 EDITION
影响因子：
--
作者：
Choi, Harry M. T.;Schwarzkopf, Maayan;Pierce, Niles A.
通讯作者：
Pierce, Niles A.
影响因子：
5.8
作者：
Chen, Zhuoyao;Wasney, Gregory A.;Bullock, Alex N.
通讯作者：
Bullock, Alex N.
影响因子：
8.8
作者：
Enchev RI;Scott DC;da Fonseca PC;Schreiber A;Monda JK;Schulman BA;Peter M;Morris EP
通讯作者：
Morris EP