Department of Biology, University of Massachusetts Boston, Boston, Massachusetts 02125.
Genetics. 2013 Dec;195(4):1307-17. doi: 10.1534/genetics.113.157859. Epub 2013 Sep 27.
The Toll signaling pathway has a highly conserved function in innate immunity and is regulated by multiple factors that fine tune its activity. One such factor is β-arrestin Kurtz (Krz), which we previously implicated in the inhibition of developmental Toll signaling in the Drosophila melanogaster embryo. Another level of controlling Toll activity and immune system homeostasis is by protein sumoylation. In this study, we have uncovered a link between these two modes of regulation and show that Krz affects sumoylation via a conserved protein interaction with a SUMO protease, Ulp1. Loss of function of krz or Ulp1 in Drosophila larvae results in a similar inflammatory phenotype, which is manifested as increased lamellocyte production; melanotic mass formation; nuclear accumulation of Toll pathway transcriptional effectors, Dorsal and Dif; and expression of immunity genes, such as Drosomycin. Moreover, mutations in krz and Ulp1 show dosage-sensitive synergistic genetic interactions, suggesting that these two proteins are involved in the same pathway. Using Dorsal sumoylation as a readout, we found that altering Krz levels can affect the efficiency of SUMO deconjugation mediated by Ulp1. Our results demonstrate that β-arrestin controls Toll signaling and systemic inflammation at the level of sumoylation.
Toll 信号通路在先天免疫中具有高度保守的功能，并且受到多种因素的调节，这些因素可以精细地调节其活性。β-arrestin Kurtz（Krz）就是这样一个因子，我们之前曾在黑腹果蝇胚胎中发现它可以抑制发育中的 Toll 信号。控制 Toll 活性和免疫系统稳态的另一个层次是通过蛋白质 SUMO 化。在这项研究中，我们发现这两种调节方式之间存在联系，并表明 Krz 通过与 SUMO 蛋白酶 Ulp1 的保守蛋白相互作用影响 SUMO 化。在果蝇幼虫中，krz 或 Ulp1 的功能丧失会导致类似的炎症表型，表现为 Lamellocyte 产生增加；黑色素质形成；Toll 通路转录效应因子 Dorsal 和 Dif 的核积累；以及免疫基因，如 Drosomycin 的表达。此外，krz 和 Ulp1 的突变显示出剂量敏感的协同遗传相互作用，这表明这两种蛋白参与了相同的途径。使用 Dorsal SUMO 化作为读出结果，我们发现改变 Krz 水平会影响 Ulp1 介导的 SUMO 去共轭效率。我们的结果表明，β-arrestin 通过 SUMO 化在 Toll 信号和全身炎症水平上进行控制。
