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Researchers have discovered a previously unknown signalling cascade that determines how powerful our innate immune system responds to virus infections. This discovery has broad implications for inflammatory diseases, cancer, and neurodegeneration / publication in ’Nature Cell Biology‘
Innate immune sensors – known as pattern recognition receptors (PRRs) – detect specific molecular components of bacterial or viral intruders. The PRRs forward the signals which results in the production of interferons, which in turn guide the immune cells. However, until now the precise mechanism of how these signals are forwarded has remained enigmatic.
In a new study, an international team of researchers led by Dr Eva Rieser and Professor Henning Walczak from the University of Cologne have shown that the enzyme ANKIB1 is crucial for the process of innate immune signalling. The study reveals that ANKIB1 catalyses a highly specific type of molecular modification called K11-ubiquitin, which acts as a docking platform to assemble the machinery that turns on type I and type III interferons, the body’s frontline antiviral messengers. The study ‘Lysine 11-ubiquitination drives Type-I/III Interferon induction by cGAS–STING and Toll-Like Receptors 3 and 4’ was published in Nature Cell Biology.
The research finding solves a long‑standing puzzle in innate immunity and provides opportunities for the future development of completely new therapies for various devastating diseases. ‘We discovered that ANKIB1 decides when the alarm clock for immune cells sounds and, importantly, how loud this wake-up call will be’, says Henning Walczak, Alexander-von-Humboldt Professor of Biochemistry and Director of the Institute of Biochemistry I of the University of Cologne’s Faculty of Medicine and Principal Researcher at the CECAD Cluster of Excellence in Aging Research and the Cancer Institute of University College London. ‘With K63- and M1-ubiquitin, so far only two letters of the ubiquitin signalling code were known. With the discovery of K11-ubiquitin as the third letter of the ubiquitin alphabet, we are now a decisive step closer to the deciphering of the ubiquitin code of cellular signalling’ says Dr Eva Rieser, a biochemist and immunologist at the Institute of Biochemistry of the University of Cologne’s Faculty of Mathematics and Natural Sciences.
In experiments with cell culture and animal models, the researchers confirmed that the newly discovered signalling axis, namely ANKIB1–K11‑Ubiquitin–OPTN–TBK1–IRF3, is crucial for alerting the immune system to virus infections. The team found that ANKIB1 is essential to fight off an infection by herpes simplex virus I, the virus that causes cold sores. In its absence, mice cannot produce the interferon necessary to alert the immune system so that it can fight the infection. The consequence is drastic: this otherwise rather harmless virus leads to the death of the mice.
However, too much interferon is responsible for a set of severe inflammatory diseases. Strikingly, in an in-vivo model of one such interferonopathy, mice devoid of ANKIB1 survived an otherwise lethal inflammation. Together, these results demonstrate the essential role of ANKIB1 for both: physiologically required and pathological interferon responses.
Boosting the immune attack on cancer
‘Although the work is grounded in fundamental biochemistry and immunology, it also has important implications for cancer, as this signalling cascade is central to the dialogue between tumour and immune cells’, says Professor Julian Pardo from the Aragón Health Research Institute, CIBERINFEC and the University of Zaragoza, Spain, a collaborator on this study. Many tumours co‑opt the chronic activation of innate immune pathways, particularly those triggered by cGAS–STING and different TLRs. This creates a chronic inflammation in the ecosystem in which the cancer cells reside so that an effective immune attack on the cancer is dampened or even prevented.
By pinpointing ANKIB1 and the K11-ubiquitin it generates as decisive for interferon induction by these immune receptors, this study provides a new handle on understanding how cancer cells may tune these pathways to their advantage and, importantly, how this balance could be reset therapeutically. Modulating ANKIB1 activity could, in principle, help ‘re‑educate’ the immune landscape within tumours, either by enhancing interferon responses to support immunotherapy, or by restraining excessive inflammation that fuels immune exhaustion and tissue damage.
A new entry point into inflammatory neurological diseases
Chronic, low‑grade activation of innate immune sensors in the brain has moreover emerged as a common theme in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, where interferon signalling has been shown to contribute to neuroinflammation and neuronal loss. By defining ANKIB1 as the enabler of these interferon pathways, the study offers a conceptual framework for dissecting how inflammatory signalling is synchronised in the brain and sheds light on how aberrant interferon production may result in neurodegeneration.
“This level of mechanistic resolution, down to the exact ubiquitin chain type and the enzyme that generates it, is what turns a complex immune cascade into a concrete, druggable process,’ Walczak explains. This discovery may therefore lead to future therapies and clinical practice for a variety of diseases. Rather than globally suppressing the immune system, which would lead to a shutting down of all essential host defence, inhibition of ANKIB1’s catalytic activity or the promotion of its degradation would be sufficient to treat interferon‑driven auto-inflammatory and -immune conditions. At the same time, the transient boost of ANKIB1 activity or stabilisation of K11‑ubiquitin could be employed in settings where stronger antiviral or antitumor immunity is desired.
This work is the result of close collaboration with the groups of Professor Julian Pardo, Professor Antonio Alcamí from the Center for Molecular Biology Severo Ochoa, Spanish National Research Council (CSIC), in Madrid, Spain, and Professor Brian Ferguson from the University of Cambridge, UK, who contributed crucial in-vivo and in-vitro infection models and virological expertise.
Professor Dr Henning Walczak
Institute of Biochemistry I
+49 221 478 84076
h.walczak@uni-koeln.de
https://www.nature.com/articles/s41556-026-01886-z
https://biochemie-med.uni-koeln.de/en/research/research-groups/walczak-lab
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