X-KINGDOM-MIF - Cross-kingdom analysis of macrophage migration inhibitory factor (MIF) functions

趋化素样介质巨噬细胞移动抑制因子(MIF)是一种重要的人类疾病标志物，是感染性休克、结肠炎、疟疾、类风湿性关节炎、动脉粥样硬化等炎症性、感染性和免疫性疾病以及肿瘤发生的关键介质。由于对MIF的S病理生物学的不完全机械性理解，MIF研究中出现的翻译应用被推迟。引人注目的是，MIF是一种进化上保守的蛋白质，在各个王国都有发现。尽管分子大小有限，缺乏可察觉的模块结构域，但MIF已被发现具有多个序列和三维结构基序，其中包括两个催化位点，这为该蛋白提供了惊人的功能复杂性。近年来，申请者在阐明MIF结构及其在人类和植物疾病中的作用方面做出了重大贡献，并在植物MIF的电子表征方面进行了全面的研究。在这些发现的背景下，这项ANR-DFG联合提案的目的是研究人类、植物和寄生虫(蚜虫)起源的MIF之间的分子联系，以确定在调节王国之间的免疫反应中潜在的保守功能。申请者结合了人类MIF免疫调节机制和昆虫病理生物学方面的专业知识，以及拟南芥和大麦比较植物免疫和分子遗传学方面的长期专业知识，以研究这种跨物种/王国方法中MIF的功能和结构特征。因此，他们代表着一个独特的跨学科团队，将MIF生物化学、生物学和病理生物学方面的深入专业知识与植物遗传学、生物技术和传染病研究相结合。该合作项目将使我们能够第一次阐明植物和昆虫MIF的作用，以及不同王国之间共享与不同主题的功能相关性。我们将系统地利用MIF的S结构-功能谱的跨域分析来更好地了解MIF在传染病和植物免疫中的作用机制。此外，该提议将引发对MIF家族免疫逃避机制和进化史的新研究。

The chemokine-like mediator macrophage migration inhibitory factor (MIF) is a prominent human disease marker and a pivotal mediator of inflammatory, infectious and immune diseases including septic shock, colitis, malaria, rheumatoid arthritis, and atherosclerosis, as well as tumorigenesis. Translational applications emerging from MIF research have been delayed because of an incomplete mechanistic understanding of MIF´s pathobiology. Strikingly, MIF is an evolutionarily conserved protein that is found across kingdoms. Despite of its limited molecular size and lack of appreciable modular domains, MIF has been found to exhibit several sequential and three-dimensional structural motifs including two catalytic sites that provide this protein with a surprising functional complexity. In recent years, the applicants have significantly contributed to the elucidation of MIF structure and its role in human and plant disease and have performed comprehensive in silico characterization of plant MIFs. In the context of these findings, it is the aim of this joint ANR-DFG proposal to study the molecular links between MIF of human, plant and parasite (aphid) origin to identify potentially conserved functions in the regulation of immune responses between kingdoms. The applicants combine expert knowledge in immune regulatory mechanisms of human MIF and insect pathobiology as well as long-standing expertise in comparative plant immunity and molecular genetics of Arabidopsis thaliana and barley to study MIF functional and structural features in this cross-species/kingdom approach. They thus represent a unique interdisciplinary team combining in-depth expertise on MIF biochemistry, biology, and pathobiology, with plant genetics and biotechnology and infectious disease research. The collaborative project will enable us to shed first light on the role of plant and insect MIFs and on the functional relevance of the shared versus distinct motifs between the different kingdoms. We will systematically utilize the cross-kingdom analysis of MIF´s structure-function profile to better understand the mechanisms of MIF in infectious disease and plant immunity. In addition, the proposal will spark novel research into immune evasion mechanisms and evolutionary history of the MIF family.