ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213

Juraj Ahel, Arda Balci, Victoria Faas, Daniel B. Grabarczyk, Roosa Harmo, Daniel R. Squair, Jiazhen Zhang, Elisabeth Roitinger, Frederic Lamoliatte, Sunil Mathur, Luiza Deszcz, Lillie E. Bell, Anita Lehner, Thomas L. Williams, Hanna Sowar, Anton Meinhart, Nicola T. Wood, Tim Clausen (), Satpal Virdee () and Adam J. Fletcher ()
Additional contact information
Juraj Ahel: Vienna BioCenter
Arda Balci: University of Glasgow
Victoria Faas: Vienna BioCenter
Daniel B. Grabarczyk: Vienna BioCenter
Roosa Harmo: University of Glasgow
Daniel R. Squair: University of Dundee
Jiazhen Zhang: University of Dundee
Elisabeth Roitinger: Vienna BioCenter
Frederic Lamoliatte: University of Dundee
Sunil Mathur: University of Dundee
Luiza Deszcz: Vienna BioCenter
Lillie E. Bell: Vienna BioCenter
Anita Lehner: Vienna BioCenter
Thomas L. Williams: Vienna BioCenter
Hanna Sowar: University of Glasgow
Anton Meinhart: Vienna BioCenter
Nicola T. Wood: University of Dundee
Tim Clausen: Vienna BioCenter
Satpal Virdee: University of Dundee
Adam J. Fletcher: University of Glasgow

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The giant E3 ubiquitin ligase RNF213 is a conserved component of mammalian cell-autonomous immunity, limiting the replication of bacteria, viruses and parasites. To understand how RNF213 reacts to these unrelated pathogens, we employ chemical and structural biology to find that ATP binding to its ATPases Associated with diverse cellular Activities (AAA) core activates its E3 function. We develop methodology for proteome-wide E3 activity profiling inside living cells, revealing that RNF213 undergoes a reversible switch in E3 activity in response to cellular ATP abundance. Interferon stimulation of macrophages raises intracellular ATP levels and primes RNF213 E3 activity, while glycolysis inhibition depletes ATP and downregulates E3 activity. These data imply that ATP bears hallmarks of a danger/pathogen associated molecular pattern, coordinating cell-autonomous defence. Furthermore, quantitative labelling of RNF213 with E3-activity probes enabled us to identify the catalytic cysteine required for substrate ubiquitination and obtain a cryo-EM structure of the RNF213-E2-ubiquitin conjugation enzyme transfer intermediate, illuminating an unannotated E2 docking site. Together, our data demonstrate that RNF213 represents a new class of ATP-dependent E3 enzyme, employing distinct catalytic and regulatory mechanisms adapted to its specialised role in the broad defence against intracellular pathogens.

Date: 2025
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DOI: 10.1038/s41467-025-59444-4

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