Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4 PMID: 41792265

ADC Targets in Oncology

2026-04-10

Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4

Nat Cell Biol. 2026 Mar;28(3):608-621. doi: 10.1038/s41556-026-01886-z.

Alexis Betrancourt ^# ¹ ² ³ , M Talha Cinko ^# ¹ ² , Ana Beatriz Varanda ¹ ² , Maykel Arias ⁴ ⁵ ⁶ , Iratxe Uranga-Murillo ⁴ ⁵ ⁶ , Natacha Peña ⁴ ⁵ ⁶ , Lucia-Maria Kaps ¹ ² , Long Fung Chau ⁷ , Bianca Buratti ¹ ² , Johannes Brägelmann ⁸ ⁹ , Diego de Miguel ¹ ² ³ ⁵ , Kerstin Becker ¹⁰ , Ramona Casper ¹⁰ , Rocio Martin ¹¹ , Antonio Alcami ¹¹ , Brian J Ferguson ⁷ , Julian Pardo ⁴ ⁵ ⁶ , Eva Rieser ¹² ¹³ ¹⁴ ¹⁵ , Henning Walczak ¹⁶ ¹⁷ ¹⁸

Affiliations

1. Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Faculty of Medicine, University of Cologne, Cologne, Germany.
2. Cell Death, Inflammation and Immunity Laboratory, CECAD Cluster of Excellence, University of Cologne, Cologne, Germany.
3. Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK.
4. CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
5. Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain.
6. Department of Microbiology, Paediatrics, Radiology and Preventive Medicine and Public Health, University of Zaragoza, Zaragoza, Spain.
7. Department of Pathology, University of Cambridge, Cambridge, UK.
8. Mildred Scheel School of Oncology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.
9. Medical Clinic III for Oncology, Hematology, Immune-Oncology and Rheumatology, University Hospital of Bonn, Bonn, Germany.
10. Cologne Centre for Genomics, Medical Faculty, University of Cologne, Cologne, Germany.
11. Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
12. Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Faculty of Medicine, University of Cologne, Cologne, Germany. [email protected].
13. Cell Death, Inflammation and Immunity Laboratory, CECAD Cluster of Excellence, University of Cologne, Cologne, Germany. [email protected].
14. Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK. [email protected].
15. Institute of Biochemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany. [email protected].
16. Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Faculty of Medicine, University of Cologne, Cologne, Germany. [email protected].
17. Cell Death, Inflammation and Immunity Laboratory, CECAD Cluster of Excellence, University of Cologne, Cologne, Germany. [email protected].
18. Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK. [email protected].
# Contributed equally.

Abstract

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.