Researchers from the University of Cologne, in collaboration with international partners, have identified the enzyme ANKIB1 as a critical regulator in innate immune signaling. The study, led by Dr Eva Rieser and Professor Henning Walczak, provides new insights into how the body’s immune system detects and responds to viral infections.
Pattern recognition receptors (PRRs) are responsible for identifying molecular patterns associated with bacteria or viruses. These sensors trigger signals that result in the production of interferons, proteins that guide immune cells to respond to infection. Until now, the details of how these signals were transmitted remained unclear.
The research team discovered that ANKIB1 facilitates a specific type of molecular modification known as K11-ubiquitin. This modification acts as a docking site for assembling components necessary to activate type I and type III interferons—key elements in antiviral defense. Their findings were published under the title 'Lysine 11-ubiquitination drives Type-I/III Interferon induction by cGAS–STING and Toll-Like Receptors 3 and 4' in Nature Cell Biology.
“We discovered that ANKIB1 decides when the alarm clock for immune cells sounds and, importantly, how loud this wake-up call will be,” said Henning Walczak, Alexander-von-Humboldt Professor of Biochemistry at the University of Cologne and Principal Researcher at both CECAD Cluster of Excellence in Aging Research and University College London’s Cancer Institute.
Dr Eva Rieser added: “With K63- and M1-ubiquitin, so far only two letters of the ubiquitin signaling 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 signaling.”
Laboratory experiments using cell cultures and animal models confirmed that ANKIB1 is essential for alerting immune defenses against viral threats such as herpes simplex virus I. In its absence, mice failed to produce enough interferon to mount an effective response; this resulted in fatal outcomes from infections typically considered mild.
Conversely, excessive interferon activity can cause severe inflammatory diseases. In mouse models lacking ANKIB1 exposed to conditions mimicking such inflammation (interferonopathy), survival rates improved compared to those with normal ANKIB1 function. These results underscore ANKIB1's central role in balancing both protective and pathological interferon responses.
Professor Julian Pardo from Aragón Health Research Institute highlighted broader implications: “Although the work is grounded in fundamental biochemistry and immunology, it also has important implications for cancer, as this signaling cascade is central to the dialogue between tumor and immune cells.” He noted that certain cancers exploit chronic activation of innate immunity pathways—such as those triggered by cGAS–STING—to evade effective immune attacks through sustained inflammation within tumors.
By identifying ANKIB1’s role in generating K11-ubiquitin required for these processes, researchers suggest new avenues for cancer therapy aimed at recalibrating immune responses within tumors—either enhancing them during immunotherapy or dampening harmful inflammation when needed.
The study also touches on neurodegenerative diseases like Alzheimer’s and Parkinson’s disease where persistent activation of innate immunity contributes to neuroinflammation. Defining ANKIB1's function provides a framework for understanding inflammatory signaling synchronization in brain disorders linked with aberrant interferon production.
“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 explained. He suggested future therapies could target ANKIB1 specifically rather than suppressing overall immunity—potentially treating autoimmune conditions or boosting antiviral/tumor immunity selectively.
The research involved close cooperation among groups led by Professor Julian Pardo; Professor Antonio Alcamí from Spain’s Center for Molecular Biology Severo Ochoa (CSIC); and Professor Brian Ferguson from Cambridge University who contributed expertise on infection models.
