170198 20260407115449.0 doi 10.1038/s41556-026-01886-z sideral 148703 ART-2026-148703 eng Betrancourt, Alexis Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS–STING and Toll-like receptors 3 and 4 2026 Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP–AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS–STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS–STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS–STING, TLR3 and TLR4. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignar info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Cinko, M. Talha Varanda, Ana Beatriz Arias, Maykel Universidad de Zaragoza (orcid)0000-0002-9730-2210 Uranga-Murillo, Iratxe Peña, Natacha Universidad de Zaragoza Kaps, Lucia-Maria Chau, Long Fung Buratti, Bianca Brägelmann, Johannes de Miguel, Diego Becker, Kerstin Casper, Ramona Martin, Rocio Alcami, Antonio Ferguson, Brian J. Pardo, Julian Universidad de Zaragoza (orcid)0000-0003-0154-0730 Rieser, Eva Walczak, Henning 1011 566 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Inmunología 1013 830 Universidad de Zaragoza Dpto. Cirugía Área Traumatología y Ortopedia 28, 3 (2026), 608-621 Nat. cell biol. NATURE CELL BIOLOGY 1465-7392 8753344 http://zaguan.unizar.es/record/170198/files/texto_completo.pdf Versión publicada 2461759 http://zaguan.unizar.es/record/170198/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:170198 articulos driver 2026-03-26-14:31:32 ARTICLE