Dysregulated sensing of self nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type-I interferons by innate cells. Here we show that complexes of self-DNA and autoantibodies (DNA-IC) contribute to elevated interferon levels via activation of the cGAS-STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp causes a delay in endolysosomal maturation and prolongs the transit time of ingested DNA-IC. Stalling in maturation-defective organelles facilitates leakage of DNA-IC into the cytosol, promoting activation of the TBK1-STING pathway. Genetic deletion of STING, STING and cGAS chemical inhibitors abolish interferon production and rescue systemic activation of interferon stimulated genes in vivo. These data unveil the contribution of cytosolic self-nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodelling to prevent innate activation.
Giulia Maria Piperno, Asma Naseem, Giulia Silvestrelli, Roberto Amadio, Nicoletta Caronni, Karla Evelia Cervantes Luevano, Nalan Liv, Judith Klumperman, Andrea Colliva, Hashim Ali, Francesca Graziano, Philippe Benaroch, Hans Haecker, Richard N. Hanna, Federica Benvenuti