RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signaling

Heilig, R.; Glover, H.; Mellor, C.; Cloix, C.; McIlwraith, M.; Paul, N.; Thomason, P.; Prasad, B.; Ahmed, A.; Dupuis, H.; Dalseno, D.; Smith, L.; Hamilton, J.; Hall-Younger, E.; Vringer, E.; Buetow, L.; Roca-Portoles, A.; Montes-Gomez, A.; Clark, G.; Black, A.; Lilla, S.; Zanivan, S.; Carlin, L.; Helgason, V.; Huang, D.; Tait, S. W.

doi:10.64898/2026.09.21.752888

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bioRxiv · 10.64898/2026.09.21.752888

RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signaling

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Abstract

Through mitochondrial outer membrane permeabilization (MOMP), mitochondria are central to apoptosis. MOMP is pro-inflammatory, impacting diverse processes including anti-tumor immunity and cellular senescence. Despite this, how damaged mitochondria activate inflammation remains unclear. Recent studies have shown that following MOMP, mitochondria are extensively ubiquitinated activating pro-inflammatory NF-{kappa}B signaling. We identify the E3 ligase, RNF213, as essential for pro-inflammatory mitochondrial ubiquitination following MOMP. RNF213 has an established role in pro- inflammatory, cell-autonomous immunity to bacteria and other pathogens. We discover that RNF213 is required for mitochondrial M1-linked (linear) ubiquitination. Interestingly, this was found to be independent of the canonical M1-ubiquitin ligase complex LUBAC. RNF213 can directly catalyze M1-linked ubiquitination. By promoting mitochondrial M1-linked ubiquitination, RNF213 initiates the recruitment of the essential NF{kappa}B adaptor molecule, NEMO, and subsequently activates pro-inflammatory NF-{kappa}B signaling. Collectively, our findings highlight striking similarities between how cells detect damaged mitochondria and intracellular pathogens, leading to inflammation.

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Heilig, R., Glover, H., Mellor, C., Cloix, C., McIlwraith, M., Paul, N., Thomason, P., Prasad, B., Ahmed, A., Dupuis, H., Dalseno, D., Smith, L., Hamilton, J., Hall-Younger, E., Vringer, E., Buetow, L., Roca-Portoles, A., Montes-Gomez, A., Clark, G., Black, A., Lilla, S., Zanivan, S., Carlin, L., Helgason, V., Huang, D., Tait, S. W.. 2026-09-22. RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signaling. https://doi.org/10.64898/2026.09.21.752888

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