Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
Biochem Soc Trans. 2012 Feb;40(1):215-8. doi: 10.1042/BST20110629.
The anti-inflammatory effects of the prototypical second messenger cAMP have been extensively documented in multiple cell types. One mechanism by which these effects are achieved is via Epac1 (exchange protein directly activated by cAMP 1)-dependent induction of SOCS-3 (suppressor of cytokine signalling 3), which binds and inhibits specific class I cytokine receptors. One important aspect of SOCS-3 functionality is its role as the specificity determinant within an E3 ubiquitin ligase complex which targets cellular substrates for polyubiquitylation and proteasomal degradation. In the present review, we describe key inhibitory processes that serve to reduce cytokine receptor signalling, focusing primarily on SOCS protein function and regulation. We also outline a strategy we have developed to identify novel ubiquitylated substrates for the Epac1-inducible SOCS-3 E3 ubiquitin ligase complex following purification of the ubiquitinome. It is anticipated that identifying substrates for the Epac1-regulated SOCS-3 E3 ubiquitin ligase, and assessment of their functional significance, may pinpoint new sites for therapeutic intervention that would achieve therapeutic efficacy of cAMP-elevating drugs while minimizing the adverse effects usually associated with these agents.
典型的第二信使 cAMP 的抗炎作用在多种细胞类型中得到了广泛的证实。这些作用实现的一种机制是通过 Epac1（cAMP 直接激活交换蛋白 1）依赖性诱导 SOCS-3（细胞因子信号转导抑制因子 3），SOCS-3 结合并抑制特定的 I 类细胞因子受体。SOCS-3 功能的一个重要方面是其作为 E3 泛素连接酶复合物内的特异性决定因素的作用，该复合物将细胞底物靶向多泛素化和蛋白酶体降解。在本综述中，我们描述了主要用于减少细胞因子受体信号的关键抑制过程，主要集中在 SOCS 蛋白的功能和调节上。我们还概述了我们开发的一种策略，即在纯化泛素组后，鉴定 Epac1 诱导的 SOCS-3 E3 泛素连接酶复合物的新泛素化底物。预计鉴定 Epac1 调节的 SOCS-3 E3 泛素连接酶的底物，并评估其功能意义，可能会指出新的治疗干预靶点，从而实现 cAMP 升高药物的治疗效果，同时最大限度地减少这些药物通常伴随的不良反应。
