Candido-Ferreira Ivan Lavander, Kronenberger Thales, Sayegh Raphael Santa Rosa, Batista Isabel de Fátima Correia, da Silva Junior Pedro Ismael
Special Laboratory for Applied Toxinology (LETA), Center of Toxins, Immune-Response and Cell Signaling (CeTICS), Butantan Institute, São Paulo, São Paulo, Brazil; Biosciences Institute, University of São Paulo, São Paulo, São Paulo, Brazil.
Department of Parasitology, Biomedical Sciences Institute, University of São Paulo , São Paulo, São Paulo , Brazil.
Front Immunol. 2017 Jan 9;7:664. doi: 10.3389/fimmu.2016.00664. eCollection 2016.
The ubiquitin-proteasome pathway (UPP) is a hallmark of the eukaryotic cell. In jawed vertebrates, it has been co-opted by the adaptive immune system, where proteasomal degradation produces endogenous peptides for major histocompatibility complex class I antigen presentation. However, proteolytic products are also necessary for the phylogenetically widespread innate immune system, as they often play a role as host defense peptides (HDPs), pivotal effectors against pathogens. Here, we report the identification of the arachnid HDP oligoventin, which shares homology to a core member of the UPP, E3 ubiquitin ligases. Oligoventin has broad antimicrobial activity and shows strong synergy with lysozymes. Using computational and phylogenetic approaches, we show high conservation of the oligoventin signature in HECT E3s. simulation of HECT E3s self-proteolysis provides evidence that HDPs can be generated by fine-tuned 26S proteasomal degradation, and therefore are consistent with the hypothesis that oligoventin is a cryptic peptide released by the proteolytic processing of an Nedd4 E3 precursor protein. Finally, we compare the production of HDPs and endogenous antigens from orthologous HECT E3s by proteasomal degradation as a means of analyzing the UPP coupling to metazoan immunity. Our results highlight the functional plasticity of the UPP in innate and adaptive immune systems as a possibly recurrent mechanism to generate functionally diverse peptides.
泛素-蛋白酶体途径（UPP）是真核细胞的一个标志。在有颌脊椎动物中，它已被适应性免疫系统所利用，在该系统中，蛋白酶体降解产生用于主要组织相容性复合体I类抗原呈递的内源性肽段。然而，蛋白水解产物对于在系统发育上广泛存在的先天性免疫系统也是必需的，因为它们通常作为宿主防御肽（HDP）发挥作用，是对抗病原体的关键效应分子。在此，我们报告了蛛形纲动物HDP寡聚蛋白的鉴定，它与UPP的一个核心成员E3泛素连接酶具有同源性。寡聚蛋白具有广泛的抗菌活性，并与溶菌酶表现出强烈的协同作用。通过计算和系统发育方法，我们表明寡聚蛋白特征在HECT E3s中具有高度保守性。对HECT E3s自蛋白水解的模拟提供了证据，表明HDPs可由微调的26S蛋白酶体降解产生，因此与寡聚蛋白是由Nedd4 E3前体蛋白的蛋白水解加工释放的一种隐蔽肽这一假设相一致。最后，我们比较了通过蛋白酶体降解从直系同源HECT E3s产生的HDPs和内源性抗原，以此作为分析UPP与后生动物免疫耦合的一种手段。我们的结果突出了UPP在先天性和适应性免疫系统中的功能可塑性，这可能是一种产生功能多样肽段的反复出现的机制。
