{
  "abstract": "RNF213 is a giant AAA+ ubiquitin ligase that serves as a central hub of innate immunity, responding to diverse stress signals with broad reactivity1-6. This versatility demands tight regulation, and its failure causes disease, such as Moyamoya angiopathy7-10 and cancer progression11-13. 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-{kappa}B 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.",
  "abstract_shown": true,
  "affiliations": [
    "Research Institute of Molecular Pathology"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "L. E. Bell"
    },
    {
      "name": "V. Faas"
    },
    {
      "name": "D. B. Grabarczyk"
    },
    {
      "name": "M. H. Wallnöfer"
    },
    {
      "name": "E. Kohoutkova"
    },
    {
      "name": "L. Deszcz"
    },
    {
      "name": "T. L. Williams"
    },
    {
      "name": "A. Meinhart"
    },
    {
      "name": "H. Scott"
    },
    {
      "name": "F. Riant"
    },
    {
      "name": "C. Aloui"
    },
    {
      "name": "M. Kossorotoff"
    },
    {
      "name": "L. Lacan"
    },
    {
      "name": "F. Godart"
    },
    {
      "name": "E. Tournier-Lasserve"
    },
    {
      "name": "A. J. Fletcher"
    },
    {
      "affs": [
        0
      ],
      "name": "T. Clausen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aeq96t8d8ycg9.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.07.26364583",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364583v1.full",
  "id": "aeq96t8d8ycg9",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364583v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "cardiovascular medicine"
    ],
    [
      "openalex",
      "1312|Ubiquitin and proteasome pathways"
    ]
  ],
  "openalex": "W7221449826",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364583v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/aeq96t8d8ycg9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:38Z",
      "native_id": "10.64898/2026.10.07.26364583",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364583v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:cardiovascular medicine",
      "subfield": "cardiovascular"
    }
  ],
  "title": "A tuneable structural switch controls RNF213 activity and is bypassed in Moyamoya disease",
  "title_text": "A tuneable structural switch controls RNF213 activity and is bypassed in Moyamoya disease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:38Z",
  "url": "https://research.draconitic.com/paper/aeq96t8d8ycg9",
  "venue": "medRxiv",
  "versions": []
}