NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates
Abstract TBK1 kinase is a central regulator of type I IFN production. Upon activation of the IFN-β induction pathway, TBK1-adaptor proteins (NAP1, SINTBAD, TANK) form liquid condensates. We show that NAP1 condensates concentrate TBK1. Using NAP1 KO cell lines, we demonstrate that NAP1 exerts a dual effect on TBK1 activity. Initially, NAP1 binds TBK1 and increases its activity, promoting IFN pathway activation. Subsequently, TBK1-mediated phosphorylation of NAP1 induces the formation of condensates. These NAP1 condensates concentrate both TBK1 and the phosphatase PP2A, which dephosphorylates and consequently deactivates TBK1, thus limiting IFN induction. Additionally, in patients with lupus or interferonopathies, we identify NAP1 variants unable to form condensates upon danger signal exposure, which sustain TBK1 activation without limiting its activity. This study reveals a mode of regulating a signaling pathway through condensate formation and provides a potential molecular explanation for immune dysregulation associated with NAP1 variants in certain patients with interferonopathies.
Authors
- Alice Lepelley (ORCID: https://orcid.org/0000-0001-8656-7291)
- Camille Brunaud
- Benjamin Leonardon (ORCID: https://orcid.org/0000-0003-4790-9070)
- Quentin Riller (ORCID: https://orcid.org/0000-0003-3323-0235)
- Yanick Joseph Crow (ORCID: https://orcid.org/0000-0001-7211-7564)
- Darragh Duffy (ORCID: https://orcid.org/0000-0002-8875-2308)
- Yves Gaudin (ORCID: https://orcid.org/0000-0002-0122-2954)
- Karine Brochard
- Luís Seabra (ORCID: https://orcid.org/0000-0002-4678-3026)
- Alexandre Bélot (ORCID: https://orcid.org/0000-0003-4902-5332)
- Damien Glon (ORCID: https://orcid.org/0000-0001-8405-8805)
- Cécile Lagaudrière‐Gesbert (ORCID: https://orcid.org/0000-0002-0225-1554)
- Marie‐Louise Frémond (ORCID: https://orcid.org/0000-0002-2798-9141)
- Vincent Bondet (ORCID: https://orcid.org/0000-0002-6534-0984)
- Gillian Rice (ORCID: https://orcid.org/0000-0002-4223-0571)
- Frédéric Rieux‐Laucat (ORCID: https://orcid.org/0000-0001-7858-7866)
- Lucı́a Álvarez (ORCID: https://orcid.org/0000-0002-1437-5773)
- Olivier Pellé (ORCID: https://orcid.org/0000-0002-0163-6487)
- Maud Tusseau
- Ariane Guillemot
- Louise Gioja
- Zackie AKTARY
- Frédéric Rivière
- Nhat-Duong Ho
- Laïla Sago
- Brigitte Bader-Meunier
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR)
- Hospices Civils de Lyon (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- CEA Paris-Saclay (FR)
- Hypertension Institute (US)
- Institute of Genetics and Cancer (GB)
- Center for Rheumatology (US)
- Institut des Maladies Génétiques Imagine (FR)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-19
- DOI
- https://doi.org/10.1038/s41467-026-76769-w
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Biogen
- Infrastructures en Biologie Santé et Agronomie
- Institut des maladies génétiques Imagine
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- Hospices Civils de Lyon
- Université Paris-Saclay
- Assistance publique-Hôpitaux de Paris
- Directorate for Biological Sciences
- Medical Research Council
- Institute of Genetics