Crinkler effectors are iconic toxins deployed by pathogens to suppress host immunity, a function long thought exclusive to pathogenic species. Here, we uncover a striking evolutionary twist: an ADP-ribosyltransferase-associated Crinkler-like protein that has repurposed its toxin-derived activity to function as an epigenetic parasite in free-living eukaryotes, challenging the paradigm that Crinkler effectors are exclusively pathogen-restricted virulence factors. The ADP-ribosyltransferase-associated Crinkler-like protein retains a functional mono-ADP-ribosyltransferase domain homologous to diphtheria toxin, yet exhibits degeneration of N-terminal host-targeting domain, severing ties to canonical pathogenic functions. This activity enables dual subversion of host mechanisms: the ADP-ribosyltransferase-associated Crinkler-like protein mono-ADP-ribosylates the EZH2, reducing H3K27me3-mediated silencing and reactivating its own locus and adjacent transposons to drive replicative amplification; simultaneously, it modifies the immune adaptor TRAF6, suppressing NF-κB and IRF3 pathways to weaken innate immune surveillance and facilitate sustained propagation within the host genome. Notably, this parasitic strategy is countered by host detoxification: TRAF6 ubiquitinates ADP-ribosyltransferase-associated Crinkler-like protein, targeting it for proteasomal degradation. Together, our findings reveal how a toxin-derived effector escaped pathogenic contexts to evolve as a selfish genomic element, leveraging toxin-like activity to subvert epigenetic and immune barriers and redefining the evolutionary potential of Crinkler toxins as drivers of genomic conflict beyond pathogenicity.
Xu et al. (Thu,) studied this question.