Innate immune sensors known as pattern recognition receptors (PRRs) detect specific molecular components of bacterial or viral invaders. PRRs transfer signals that result in the production of interferon, which induces immune cells. However, until now, the exact mechanism of how these signals are transferred has remained a mystery.
In a new study, an international research team led by Dr Eva Rieser and Professor Henning Walchak from the University of Cologne has shown that the enzyme ANKIB1 is important for the process of innate immune signaling. This study revealed that ANKIB1 catalyzes 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 front-line antiviral messengers. The study “Lysine-11 ubiquitination promotes type I/III interferon induction by cGAS-STING and Toll-Like Receptors 3 and 4” natural cell biology.
The findings solve long-standing mysteries about innate immunity and provide an opportunity for the future development of entirely new treatments for a variety of devastating diseases. “We found that ANKIB1 determines when the immune cell alarm clock goes off and, importantly, how loud this alarm clock is,” says Henning Walzak, Alexander von Humboldt Professor of Biochemistry, Director of the First Institute of Biochemistry at the Faculty of Medicine, University of Cologne, and Principal Investigator of the CECAD Aging Research Excellence Cluster and the University College London Cancer Institute. “For K63-ubiquitin and M1-ubiquitin, only two letters of the ubiquitin signaling code are known so far. With the discovery of K11 ubiquitin, the third letter of the ubiquitin alphabet, we are decisively closer to cracking the ubiquitin code of cell signaling,” says Dr. Eva Rieser, a biochemist and immunologist at the Institute of Biochemistry at the Faculty of Mathematics and Natural Sciences at the University of Cologne.
In experiments using cell cultures and animal models, researchers confirmed that a newly discovered signaling axis, ANKIB1-K11-Ubiquitin-OPTN-TBK1-IRF3, is important in alerting the immune system to viral infection. The research team discovered that ANKIB1 is essential for fighting off infection with herpes simplex virus type I, the virus that causes cold sores. Without interferon, mice cannot produce the interferon needed to alert the immune system and fight infection. The results are dramatic. This harmless virus causes death in mice.
However, too much interferon can cause a range of severe inflammatory diseases. Remarkably, in one such in vivo model of interferonopathy, mice lacking ANKIB1 survived lethal inflammation. Taken together, these results demonstrate an important role for ANKIB1 in both physiologically necessary and pathological interferon responses.
Strengthen immune attack against cancer
“Although this study is based on basic biochemistry and immunology, it also has important implications for cancer, as this signaling cascade is central to the dialogue between tumors and immune cells,” said study co-investigator Professor Julian Pardo from the Aragon Health Institute, CIBERINFEC, and the University of Zaragoza in Spain. Many tumors take advantage of chronic activation of innate immune pathways, particularly those triggered by cGAS-STING and various TLRs. This creates chronic inflammation in the ecosystem in which cancer cells reside, weakening or even preventing an effective immune attack against cancer.
By identifying ANKIB1 and the K11 ubiquitin it produces as critical for interferon induction by these immune receptors, this study provides new clues in understanding how cancer cells favorably modulate these pathways and, importantly, how this balance can be reset therapeutically. Modulation of ANKIB1 activity could, in principle, help to ‘re-educate’ the immune landscape within tumors, either by enhancing interferon responses to support immunotherapy, or by suppressing excessive inflammation that causes immune fatigue and tissue damage.
A new gateway to inflammatory neurological diseases
Furthermore, chronic, low-grade activation of innate immune sensors in the brain has emerged as a common theme in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, and interferon signaling has been shown to contribute to neuroinflammation and neuronal cell loss. By defining ANKIB1 as an enabler of these interferon pathways, this study provides a conceptual framework for dissecting how inflammatory signaling is synchronized in the brain and reveals how aberrant interferon production can lead to neurodegeneration.
“This level of mechanistic resolution, down to the exact type of ubiquitin chain and the enzyme that produces it, turns a complex immune cascade into a concrete, druggable process,” Walczak explains. Therefore, this discovery may lead to future treatments and clinical practices for various diseases. Rather than suppressing the immune system altogether, it would shut down all essential host defenses and inhibit or promote the catalytic activity of ANKIB1. While this degradation is sufficient to treat interferon-induced autoinflammation and immune conditions, temporary enhancement of ANKIB1 activity and stabilization of K11 ubiquitin could be used when stronger antiviral or antitumor immunity is required.
This research is the result of close collaboration with the group of Professor Julian Pardo of the Spanish National Research Council (CSIC) Center for Molecular Biology in Madrid, Spain, Professor Antonio Alcami of the Severo Ochoa Center for Molecular Biology, and Professor Brian Ferguson of the University of Cambridge, UK, who contributed important in vivo and in vitro infection models and virology expertise.
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Reference magazines:
Betrancourt, A. others. (2026) Lysine 11 ubiquitination promotes type I/III interferon induction by cGAS-STING and Toll-Like receptors 3 and 4. natural cell biology. DOI: 10.1038/s41556-026-01886-z. https://www.nature.com/articles/s41556-026-01886-z
