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Oxygen-dependent regulation of E3(SCF)ubiquitin ligases and a Skp1-associated JmjD6 homolog in development of the social amoeba Dictyostelium
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2022-08-04 , DOI: 10.1016/j.jbc.2022.102305
Andrew W Boland 1 , Elisabet Gas-Pascual 2 , Braxton L Nottingham 3 , Hanke van der Wel 4 , Nitin G Daniel 5 , M Osman Sheikh 3 , Christopher M Schafer 3 , Christopher M West 6
Affiliation  

E3-SCF (Skp1/cullin-1/F-box protein) polyubiquitin ligases activate the proteasomal degradation of over a thousand proteins, but the evolutionary diversification of the F-box protein (FBP) family of substrate receptor subunits has challenged their elucidation in protists. Here we expand the FBP candidate list in the social amoeba Dictyostelium and show that the Skp1 interactome is highly remodeled as cells transition from solitary growth to multicellular development. Importantly, a subset of candidate FBPs was less represented when the posttranslational hydroxylation and glycosylation of Skp1 was abrogated by deletion of the O2 -sensing Skp1 prolyl hydroxylase PhyA. A role for this Skp1 modification for SCF activity was indicated by partial rescue of development, which normally depends on high O2 and PhyA, of phyA -knockout cells by proteasomal inhibitors. Further examination of two FBPs, FbxwD and the Jumonji C protein JcdI, suggested that Skp1 was substituted by other factors in phyA-knockout cells. Although a double-knockout of jcdI and its paralog jcdH did not affect development, overexpression of JcdI increased its sensitivity to O2. JcdI, a non-heme dioxygenase shown to have physiological O2-dependence, is conserved across protists with its F-box and other domains, and related to the human oncogene JmjD6. Sensitization of JcdI-overexpression cells to O2 depended on its dioxygenase activity and other domains, but not its F-box, which may however be the mediator of its reduced levels in wild-type relative to Skp1 modification mutant cells. The findings suggest that activation of JcdI by O2 is tempered by homeostatic down-regulation via PhyA and association with Skp1.



中文翻译:


社会阿米巴盘基网柄菌发育过程中 E3(SCF) 泛素连接酶和 Skp1 相关 JmjD6 同源物的氧依赖性调节



E3-SCF(Skp1/cullin-1/F-box 蛋白)多聚泛素连接酶可激活超过 1000 种蛋白质的蛋白酶体降解,但底物受体亚基的 F-box 蛋白 (FBP) 家族的进化多样化对它们的阐明提出了挑战。原生生物。在这里,我们扩展了社会性变形虫盘基网柄菌中的 FBP 候选列表,并表明随着细胞从单独生长过渡到多细胞发育,Skp1 相互作用组发生了高度重塑。重要的是,当通过删除 O 2感应 Skp1 脯氨酰羟化酶 PhyA 来消除 Skp1 的翻译后羟基化和糖基化时,候选 FBP 的子集较少。这种 Skp1 修饰对 SCF 活性的作用通过蛋白酶体抑制剂对phyA敲除细胞的发育的部分挽救来表明,该发育通常依赖于高 O 2和 PhyA。对两个 FBP(FbxwD 和 Jumonji C 蛋白 JcdI)的进一步检查表明,在phyA敲除细胞中 Skp1 被其他因子取代。虽然jcdI及其旁系同源物jcdH的双敲除并不影响发育,但JcdI的过度表达增加了其对O 2的敏感性。 JcdI 是一种非血红素双加氧酶,具有生理学 O 2依赖性,其 F-box 和其他结构域在原生生物中是保守的,并且与人类癌基因 JmjD6 相关。 JcdI 过表达细胞对 O 2的敏感性取决于其双加氧酶活性和其他结构域,而不是其 F-box,然而,F-box 可能是其在野生型中相对于 Skp1 修饰突变细胞水平降低的介导因素。 研究结果表明,O 2对 JcdI 的激活可通过 PhyA 的稳态下调以及与 Skp1 的关联来调节。

更新日期:2022-08-04
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