Year: 2026
Type: preprint
Abstract: RNF213 is a giant AAA+ ubiquitin ligase that serves as a central hub of innate immunity, responding to diverse stress signals with broad reactivity 1-6 . This versatility demands tight regulation, and its failure causes disease, such as Moyamoya angiopathy 7-10 and cancer progression 11-13 . How the mega-enzyme is restrained and how mutations override this control is unknown. Here, we show that RNF213 activity is regulated by a dimeric switch — a constitutive dimer that alternates between auto-inhibited and activation-competent states. In the closed dimer, intermolecular contacts bury the E3 machinery, whereas ATP binding remodels the AAA+ core to open the dimer and prime ubiquitination. Dimer conversion is tuned by ubiquitination factors, redox conditions and post-translational modifications, allowing multiple stress signals to act through the same activation mechanism. Moyamoya mutations subvert the same open-closed transition, destabilizing the autoinhibited dimer in a graded manner that tracks with clinical severity. Structural, biochemical and cellular data reveal how disease mutations allosterically disrupt the dimer interface and bypass ATP-dependent control to drive NF-κB activation and caspase-dependent apoptosis. Together, our findings reveal a tuneable dimeric switch that converts diverse stressors into graded inflammatory signalling and provide a mechanistic link between genetic predisposition, environmental triggers and Moyamoya disease.
Source: medRxiv
Authors: Lillie E. Bell, Victoria Faas, Daniel B. Grabarczyk, Moritz H. Wallnöfer, Eliska Kohoutkova, Luiza Deszcz, Thomas L. Williams, Anton Meinhart, Harry Scott, Florence Riant, Chaker Aloui, Manoelle Kossorotoff, Laure Lacan, François Godart, Elisabeth Tournier-Lasserve, Adam J. Fletcher, Tim Clausen
Institutions: University of Vienna, Research Institute of Molecular Pathology, Vienna Biocenter, Medical University of Vienna, MRC University of Glasgow Centre for Virus Research, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Centre National de la Recherche Scientifique, Inserm, Institut du Cerveau, Hôpital Necker-Enfants Malades, Institut de Psychiatrie et Neurosciences de Paris, Centre Hospitalier Universitaire de Lille, Hôpital Roger Salengro, Université Paris Cité
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221449826