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Abstract

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.

Data availability

Source data are provided with this paper. The data generated during this study are provided in the article and Supplementary information. Previously published RNA-seq data are deposited at GEO (PRJNA266803, PRJNA819945). Previously published single cell multi-omic dataset are deposited at GEO (GSE265874). Source data are provided with this paper.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 31822057 to T. X.).

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Authors and Affiliations

Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China

Tianjun Xu, Shang Geng, Xing Lv, Qianru Xing & Yuena Sun 1.

Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China

Tianjun Xu 1.

Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai, China

Tianjun Xu

Authors

1. Tianjun Xu
2. Shang Geng
3. Xing Lv
4. Qianru Xing
5. Yuena Sun

Contributions

Conceptualisation: T.X., S.G., Methodology: T.X., S.G., X.L., Q.X. Investigation: T.X., X.L., Q.X. Visualisation: T.X., S.G., X.L., Y.S. Formal analysis: S.G., X.L. Validation: S.G., X.L., Q.X. Data curation: T.X., S.G., X.L. Project administration: T.X. Writing—original draft: S.G. Writing—review: T.X., S.G., Y.S. Writing—editing: T.X., S.G., Y.S.

Corresponding author

Correspondence to Tianjun Xu.

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Xu, T., Geng, S., Lv, X. et al. AACRNL evolved from virulence factor to epigenetic parasite driving genome expansion in free-living eukaryotes. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69012-z

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Received: 04 July 2025

Accepted: 22 January 2026

Published: 29 January 2026

DOI: https://doi.org/10.1038/s41467-026-69012-z