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Abstract：
Paracrine cell-cell communication is central to all developmental processes, ranging from cell diversification to patterning and morphogenesis. Precise calibration of signaling strength is essential for the fidelity of tissue formation during embryogenesis and tissue maintenance in adults. Membrane-tethered ubiquitin ligases can control the sensitivity of target cells to secreted ligands by regulating the abundance of signaling receptors at the cell surface. We discuss two examples of this emerging concept in signaling: (1) the transmembrane ubiquitin ligases ZNRF3 and RNF43 that regulate WNT and bone morphogenetic protein receptor abundance in response to R-spondin ligands and (2) the membrane-recruited ubiquitin ligase MGRN1 that controls Hedgehog and melanocortin receptor abundance. We focus on the mechanistic logic of these systems, illustrated by structural and protein interaction models enabled by AlphaFold. We suggest that membrane-tethered ubiquitin ligases play a widespread role in remodeling the cell surface proteome to control responses to extracellular ligands in diverse biological processes.
摘要：
旁分泌细胞-细胞通讯是所有发育过程的核心,从细胞多样化到模式和形态发生。信号强度的精确校准对于成人胚胎发生和组织维持期间组织形成的保真度至关重要。膜束缚的泛素连接酶可以通过调节细胞表面的信号受体的丰度来控制靶细胞对分泌的配体的敏感性。我们讨论了信号传导中这种新兴概念的两个例子：（1）响应于R-spondin配体调节WNT和骨形态发生蛋白受体丰度的跨膜泛素连接酶ZNRF3和RNF43，以及（2）控制Hedgehog和黑皮质素受体丰度的膜募集泛素连接酶MGRN1。我们专注于这些系统的机械逻辑，由AlphaFold启用的结构和蛋白质相互作用模型说明。我们建议膜束缚的泛素连接酶在重塑细胞表面蛋白质组以控制不同生物过程中对细胞外配体的反应中起着广泛的作用。
