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ETS1 degrades Spz and ETS6 binds C106, especially impairing processing and dimerization to promote fungal colonization across diverse insect hosts.",{"@graph":14,"@context":72},[15,34,55],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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\n[www.advancedscience.com](www.advancedscience.com)  \nDual Disruption of the Immune Cytokine Spätzle Facilitates Fungal Infection of Diverse Insect Hosts  \nShuangxiu Song, Shiqin Li, Yujuan Luo, Dongxiang Wei, Junmei Shang, Hongyun Wu, Gangqi Fang, and Chengshu Wang*  \nInsect innate immunity has been well studied in Drosophila melanogaster. However, the mechanisms of immune invasion and host adaptation mediated by entomopathogens remain understudied. Here, it is reported that the Drosophila immune cytokine Spätzle (Spz, a Toll receptor ligand) can be targeted by two divergent virulence effectors (ETSs) of Metarhizium robertsii, a fungus that infects a wide range of invertebrates. Mechanistically, the M28-family aminopeptidase ETS1 degrades Spz and its mature ligand form C106, while the hypothetical protein ETS6 only binds C106. Both effectors, particularly ETS6, attenuate or disable Spz interaction with its processing enzyme, the formation of the C106 dimer, and ligand-receptor interaction. Mutagenesis of ETS6 revealed its structural uniqueness in hijacking C106. While mutant Drosophila lacking functional Spz are similarly killed by  \nwild-type and mutant strains of M. robertsii, transgenesis with either ETS1 or ETS6 reduced fly resistance to fungal colonization. Both effectors can target the sequence-divergent yet structurally similar orthologous ligands of other invertebrates, unveiling a fungal mechanism for infecting and killing diverse host species. These findings reveal a rare instance of multiple effectors targeting a single immune factor in fungus-animal interactions, and offer a mechanistic insight into the manipulation of parasite host range.  \n1. Introduction  \nInvestigation of insect immune defenses using the fruit fly Drosophila melanogaster as a model has established the Toll pathway as a critical component of antifungal immunity.[1,2] During antifungal immune responses in flies, recognition of fungal cell wall components triggers the Spätzle (Spz) processing protease (SPE) to cleave and mature the cytokine Spzinto C106, its active Toll receptor ligand form. [3,4] The ligand will then form a dimer for receptor binding to activate the expression of downstream antimicrobial peptides (AMPs) . [1,5,6] Although the pathway is widely present in different insects and other invertebrates, key immune factors such asthe Toll receptor and its ligand are highly divergent across insect orders and even species in terms of gene number and sequence identity.[7–9] A combination of conservation and divergence also characterizes mammalian Toll-like receptors and their ligands. [10] Pathology studies have unveiled the functions of various virulence-related  \nS. Song, S. Li, Y. Luo, D. Wei, J. Shang, H. Wu, G. Fang, C. Wang Key Laboratory of Insect Developmental and Evolutionary Biology, State Key Laboratory of Plant Trait Design, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology  \nChinese Academy of Sciences Shanghai 200032, China [E-mail:](E-mail: wangcs@sippe.ac.cn)[ wangcs@sippe.ac.cn](E-mail: wangcs@sippe.ac.cn)  \nS. Li, Y. Luo, H. Wu, C. Wang  \nSchool of Life Science and Technology ShanghaiTech University  \nShanghai 201210, China  \nD. Wei, C. Wang  \nCAS Center for Excellence in Biotic Interactions University of Chinese Academy of Sciences Beijing 100049, China  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202513075](https://doi.org/10.1002/advs.202513075)[ ](https://doi.org/10.1002/advs.202513075)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202513075  \ngenes in entomopathogenic fungi (EPF), mainly in the Metarhizium and Beauveria species. [11,12] For ","cbCaihJQbaqYofLK","https://ap.wps.com/l/cbCaihJQbaqYofLK","pdf",3441776,14,"English","# Introduction\n## Insect Toll pathway and Spätzle activation\n## Fungal virulence effectors in microbe–animal interactions\n## Knowledge gaps in host immune factor targeting","[{\"question\":\"What immune process does Spätzle (Spz) control in Drosophila antifungal defense?\",\"answer\":\"Spätzle is processed into C106, which forms a dimer to activate Toll receptor signaling and induce downstream antimicrobial peptide expression.\"},{\"question\":\"How do ETS1 and ETS6 from Metarhizium robertsii affect Spätzle signaling?\",\"answer\":\"ETS1 degrades Spz and disrupts C106 generation, while ETS6 binds C106 and attenuates key steps including processing-related interactions and ligand-receptor binding.\"},{\"question\":\"Do the effectors act only in Drosophila or across different insect hosts?\",\"answer\":\"Both effectors can target orthologous Toll ligand structures in other invertebrates, revealing a fungal mechanism that supports infection and killing of diverse host species.\"}]","Dual Disruption of the Immune Cytokine Spätzle Facilitates Fungal Infection of Diverse Insect Hosts | PDF",1790688852,35]