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.
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BibTeX
@article{glon2026nap1,
title = {{NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates}},
author = {Damien Glon and Quentin Riller and Lucía Álvarez and Louise Gioja and Frédéric Rivière and Benjamin Léonardon and Zackie Aktary and Ariane Guillemot and Laïla Sago and Olivier Pellé and Nhat-Duong Ho and Karine Brochard and Camille Brunaud and Luís Seabra and Gillian Rice and Vincent Bondet and Darragh Duffy and Brigitte Bader-Meunier and Marie-Louise Frémond and Alice Lepelley and Yanick Crow and Maud Tusseau and Alexandre Belot and Cécile Lagaudrière-Gesbert and Frédéric Rieux-Laucat and Yves Gaudin},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76769-w},
url = {https://pasteur.hal.science/pasteur-05764984v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates
AU - Damien Glon
AU - Quentin Riller
AU - Lucía Álvarez
AU - Louise Gioja
AU - Frédéric Rivière
AU - Benjamin Léonardon
AU - Zackie Aktary
AU - Ariane Guillemot
AU - Laïla Sago
AU - Olivier Pellé
AU - Nhat-Duong Ho
AU - Karine Brochard
AU - Camille Brunaud
AU - Luís Seabra
AU - Gillian Rice
AU - Vincent Bondet
AU - Darragh Duffy
AU - Brigitte Bader-Meunier
AU - Marie-Louise Frémond
AU - Alice Lepelley
AU - Yanick Crow
AU - Maud Tusseau
AU - Alexandre Belot
AU - Cécile Lagaudrière-Gesbert
AU - Frédéric Rieux-Laucat
AU - Yves Gaudin
PY - 2026
DA - 2026/08/19
JO - Nature Communications
DO - 10.1038/s41467-026-76769-w
UR - https://pasteur.hal.science/pasteur-05764984v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -