TBK1: The Enzyme Critical in Fighting Viruses – New Study Sheds Light on its Mechanism and Importance in Immune System Defense

According to recent research led by Prof. Martin Schlee from the University Hospital Bonn and the Cluster of Excellence ImmunoSensation at the University of Bonn, the enzyme TBK1 is a crucial element of the innate immune system that plays a pivotal role in protecting against viruses.

Individuals who experience a loss of TBK1 function due to genetic mutations are more susceptible to viral infections.

However, interestingly, patients who do not express TBK1 at all do not exhibit this clinical effect.

The discrepancy between these two outcomes has now been explained by the research team.

The study, which was published in the journal Frontiers in Immunology, revealed the mechanism behind this discrepancy.

When viral particles invade the human body, they are detected by specialized pattern recognition receptors (PRRs) that are found on the surface or inside cells. The activation of PRRs initiates a signaling pathway that culminates in the production and release of messenger molecules like cytokines and interferons. These signaling molecules then notify nearby immune cells of the viral infection and stimulate an immune response.

The activation of TANK Binding Kinase 1 (TBK1) is a crucial step in the signaling cascade that occurs when pattern recognition receptors (PRRs) detect viral particles in the human body. Once TBK1 is activated, it triggers the activation of two transcription factors that enter the nucleus and prompt the transcription of genes that produce interferons and cytokines. These messenger molecules play a critical role in the immune response to viral infections.

When there are point mutations in the TBK1 gene, it can lead to a loss of TBK1 function. In humans, this loss of function makes them more vulnerable to viral infections. However, it is interesting to note that this clinical effect is not observed when TBK1 is entirely absent and not expressed in the cell.

“Surprisingly, a complete absence of TBK1 expression in humans,” points out Prof. Martin Schlee, “is not associated with a reduced antiviral response.”

Previously, it was unclear why a complete lack of TBK1 expression was better tolerated in terms of immune function than a mutation affecting the enzyme’s kinase function. However, Bonn researchers have now shed light on this mystery.

“A second enzyme that is very similar to TBK1 plays an important role in this: the IkB kinase epsilon, or IKKepsilon for short,” adds first author Dr. Julia Wegner.

Interestingly, TBK1 has a direct effect on IKKepsilon, a novel finding revealed by the study. These two proteins share a structure that is more than 60 percent similar in sequence.

“In myeloid cells, we could show that TBK1 regulates the expression of the related kinase IKKepsilon,” says Dr. Wegner.

TBK1 is responsible for decreasing the stability of IKKepsilon, and this process occurs independently of the enzyme’s function. According to Prof. Gunther Hartmann, even nonfunctional TBK1 due to point mutation can still destabilize IKKepsilon. As a result, the kinase IKKepsilon in human immune cells undergoes continuous degradation.

The absence of TBK1 expression leads to an increase in the quantity of IKKepsilon, which allows for an antiviral immune response to occur. This mechanism ensures that the body can defend itself against viruses despite the absence of TBK1. On the other hand, when TBK1 loses its function due to point mutations, it cannot prevent the destabilization and degradation of IKKepsilon. As a result, both TBK1 and IKKepsilon become unavailable for viral defense, leading to an increased vulnerability to viral infections.

In a healthy body, the greater quantities of IKKepsilon can offset the absence of TBK1, which is especially crucial when viruses target the body’s defense mechanisms. For instance, herpes simplex virus 1 (HSV-1), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause TBK1 degradation. Furthermore, a number of bacterial species are capable of triggering TBK1 degradation.

As explained by Dr, Wegner: the findings of the study “clearly show that human immune cells have an important backup mechanism. They are able to maintain an effective antiviral response even when pathogen-induced degradation of TBK1 occurs. Furthermore, the mechanism also takes effect in the case of genetic loss of TBK1.”

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