RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signaling
- 1University of Glasgow
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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BibTeX
@misc{heilig2026rnf213,
title = {{RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signaling}},
author = {R. Heilig and H. Glover and C. Mellor and C. Cloix and M. McIlwraith and N. Paul and P. Thomason and B. Prasad and A. Ahmed and H. Dupuis and D. Dalseno and L. Smith and J. Hamilton and E. Hall-Younger and E. Vringer and L. Buetow and A. Roca-Portoles and A. Montes-Gomez and G. Clark and A. Black and S. Lilla and S. Zanivan and L. Carlin and V. Helgason and D. Huang and S. W. Tait},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.752888},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.752888v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - RNF213 M1-ubiquitinates damaged mitochondria to activate pro-inflammatory NF-κB signaling
AU - R. Heilig
AU - H. Glover
AU - C. Mellor
AU - C. Cloix
AU - M. McIlwraith
AU - N. Paul
AU - P. Thomason
AU - B. Prasad
AU - A. Ahmed
AU - H. Dupuis
AU - D. Dalseno
AU - L. Smith
AU - J. Hamilton
AU - E. Hall-Younger
AU - E. Vringer
AU - L. Buetow
AU - A. Roca-Portoles
AU - A. Montes-Gomez
AU - G. Clark
AU - A. Black
AU - S. Lilla
AU - S. Zanivan
AU - L. Carlin
AU - V. Helgason
AU - D. Huang
AU - S. W. Tait
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.752888
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.752888v1
AB - 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.
ER -