Teilen:
06.03.2026 11:00
Researchers Identify New “Molecular Switch” for Innate Immunity
Scientists have discovered a previously unknown signaling cascade that determines the strength of our innate immune system’s response to viral infections. This discovery has far-reaching implications for the treatment of inflammatory diseases, cancer, and neurodegeneration / Published in ‘Nature Cell Biology’
The body’s innate immune system relies on sensors – known as pattern recognition receptors (PRRs) – to identify specific molecules from bacterial or viral invaders. These receptors trigger signals that lead to the production of interferons, which then direct immune cells. However, the precise mechanisms behind this signaling process have remained unclear.
A new study led by Dr. Eva Rieser and Professor Henning Walczak of the University of Cologne has revealed that the enzyme ANKIB1 plays a critical role in the process of innate immune signaling. The research demonstrates that ANKIB1 catalyzes lysine-11 (K11)-linked ubiquitin chains, a highly specific molecular modification that serves as a platform for assembling the machinery that activates key antiviral messengers, Type I and Type III interferons. 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 findings resolve a long-standing puzzle in innate immunity and open new avenues for developing innovative therapies for a range of serious conditions. “We found that ANKIB1 decides when the alarm clock rings for immune cells and how loud that wake-up call is,” said Henning Walczak, Alexander von Humboldt Professor of Biochemistry and Director of the Institute for Biochemistry I at the Medical Faculty of the University of Cologne, and head of a research group at the Excellence Cluster for Aging Research CECAD and the Cancer Institute of University College London. “With K63- and M1-Ubiquitin, only two letters of the ubiquitin signal code were previously known. With the discovery of K11-Ubiquitin as a third letter of the ubiquitin alphabet, we have taken a decisive step closer to deciphering the ubiquitin code of cellular signal transduction,” explained Dr. Eva Rieser, a biochemist and immunologist at the Institute of Biochemistry of the Faculty of Mathematics and Natural Sciences at the University of Cologne.
Experiments using cell cultures and animal models confirmed that this newly discovered ANKIB1–K11-Ubiquitin–OPTN–TBK1–IRF3 signaling pathway is essential for alerting the immune system to viral infections. The team discovered that ANKIB1 is crucial for fighting off an infection with Herpes Simplex Virus I, the virus that causes cold sores. Without it, mice are unable to produce the interferon needed to alert the immune system to combat the infection, leading to a fatal outcome.
However, an excess of interferon is responsible for a number of severe inflammatory diseases. Notably, mice lacking ANKIB1 survived a typically fatal inflammation in an in vivo model of such an interferonopathy. The results demonstrate that ANKIB1 plays a central role in both physiologically necessary and pathological interferon reactions.
Boosting the Immune Attack on Cancer
“Even as the work is based on fundamental biochemical and immunological findings, it also has important implications for cancer diseases, as this signaling cascade is central to the dialogue between tumor and immune cells,” said Professor Julian Pardo from the Aragón Health Research Institute, CIBERINFEC and the University of Zaragoza in Spain, who collaborated on the study. Many tumors exploit the chronic activation of innate immune pathways – particularly those triggered by cGAS-STING and various TLRs – to their advantage, creating chronic inflammation within the ecosystem where cancer cells reside, which suppresses or even prevents an effective immune attack on the cancer.
Identifying ANKIB1 and K11-Ubiquitin as central factors in interferon induction by these immune receptors opens new approaches to understanding how cancer cells regulate these signaling pathways to their benefit and how this balance could be therapeutically restored. Manipulating ANKIB1 activity could fundamentally assist “reprogram” the immune system within tumors by either enhancing interferon responses to support immunotherapy or suppressing excessive inflammation that leads to immune exhaustion and tissue damage.
A New Avenue for Inflammatory Neurological Disorders
Chronic, low-grade activation of innate immune system sensors in the brain is also considered a common feature of neurodegenerative diseases like Alzheimer’s and Parkinson’s, where interferon signals have been shown to promote the inflammatory process in the brain and, the loss of nerve cells. The study shows that ANKIB1 and K11-Ubiquitin function as regulators of these interferon pathways, providing a conceptual framework for understanding how inflammation signals are synchronized in the brain and how aberrant interferon production promotes neurodegeneration.
“By precisely identifying the type of ubiquitin chain and the enzyme that creates it, a complex immune cascade is transformed into a clearly defined, therapeutically targetable process,” Walczak explained. This insight could enable the development of new therapies and their application in clinical practice for numerous diseases. Instead of globally suppressing the immune system, which would shut down all essential host defense mechanisms, inhibiting the catalytic activity of ANKIB1 or promoting its degradation would be sufficient to treat diseases caused by excess interferon-driven inflammation or autoimmune reactions. At the same time, temporarily increasing ANKIB1 activity or stabilizing K11-Ubiquitin could be used in situations where the immune system needs to be more strongly activated against viruses or cancer cells.
This work is the result of close collaboration with the research groups of Professor Julian Pardo in Zaragoza and Professor Antonio Alcamí from the Severo Ochoa Center for Molecular Biology of the Spanish National Research Council (CSIC) in Madrid, as well as Professor Brian Ferguson from the University of Cambridge, who contributed crucial in vivo and in vitro infection models and virological expertise.
Scientific Contact:
Professor Dr. Henning Walczak
Institute for Biochemistry I
+49 221 478 84076
[email protected]
Original Publication:
https://www.nature.com/articles/s41556-026-01886-z
Further Information:
https://biochemie-med.uni-koeln.de/forschung/arbeitsgruppen/ag-walczak
Images
Characteristics of this press release:
Journalists, Scientists
Biology, Medicine
regional
Research results
German
