Author
Listed:
- Juraj Ahel
(Vienna BioCenter)
- Arda Balci
(University of Glasgow)
- Victoria Faas
(Vienna BioCenter
a Doctoral School of the University of Vienna and the Medical University of Vienna)
- 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
a Doctoral School of the University of Vienna and the Medical University of Vienna)
- 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
Medical University of Vienna)
- Satpal Virdee
(University of Dundee)
- Adam J. Fletcher
(University of Glasgow)
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.
Suggested Citation
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. Be, 2025.
"ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213,"
Nature Communications, Nature, vol. 16(1), pages 1-19, December.
Handle:
RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59444-4
DOI: 10.1038/s41467-025-59444-4
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