A peptide toxin in ant venom mimics vertebrate EGF-like hormones to cause long-lasting hypersensitivity in mammals

Abstract

Venoms are excellent model systems for studying evolutionary processes associated with predator–prey interactions. Here, we present the discovery of a peptide toxin, MIITX2-Mg1a, which is a major component of the venom of the Australian giant red bull ant Myrmecia gulosa and has evolved to mimic, both structurally and functionally, vertebrate epidermal growth factor (EGF) peptide hormones. We show that Mg1a is a potent agonist of the mammalian EGF receptor ErbB1, and that intraplantar injection in mice causes long-lasting hypersensitivity of the injected paw. These data reveal a previously undescribed venom mode of action, highlight a role for ErbB receptors in mammalian pain signaling, and provide an example of molecular mimicry driven by defensive selection pressure.

Venomics of the Central European Myrmicine Ants Myrmica rubra and Myrmica ruginodis

“…Finally, we employed a strategy related to that of Eagles and colleagues [ 31 ] by initiating a BLAST search to identify patterns of similarity between ant EGF-like toxins and known EGF hormones across the animal kingdom ( Table 2 ). We found that five major subgroups of EGF-like toxins exist in ants.…”

“…The 113 venom components in M. ruginodis included two peptides with an EGF-like motif. These form part of a diverse family of metazoan peptide hormones that are also venom components in anemones and ants [ 14 , 22 , 31 , 46 , 47 ]. EGF-like peptides therefore provide another example of the “toxipotent” nature of peptide hormones and their potential to become weaponized as venom components [ 48 , 49 , 50 , 51 , 52 , 53 ].…”

“…Several EGF-like toxins have recently been described in the ant subfamilies Myrmeciinae ( M. gullosa and M. chrysogaster ), Ectatomminae ( R. metallica ), Myrmicinae ( Myrmica sulconodus, M. rubra, M. ruginodis, M. rubida, Pogonomyrmex californicus and Pogonomyrmex barbatus ) and Formicinae ( Formica aquilonia ) [ 14 , 22 , 31 ]. With the exception of the three peptides from M. gulosa, M. chrysogaster and M. rubida , all the EGF-like toxins were retrieved from whole-body transcriptomes or genomes, so it is unclear if they are translated into venom proteins [ 31 ]. In our study, we found that nine EGF-like toxins were expressed in the venom gland, two of which were also detected at the proteomic level.…”

“…The most interesting components identified in the venom systems of M. rubra and M. ruginodis were the EGF-like toxins, whose biological functions remain unclear. The corresponding myrmecine peptides (MIITX-clade) were recently identified as members of this venom protein family [ 31 ]. They showed no activity against insects but induced pain in mice for several days [ 31 ].…”

“…The corresponding myrmecine peptides (MIITX-clade) were recently identified as members of this venom protein family [ 31 ]. They showed no activity against insects but induced pain in mice for several days [ 31 ]. The MIITX EGF-like toxins may therefore have evolved to mimic HBEGF hormones, resulting in their remarkable algogenic effects by activating mammalian ErbB receptors.…”