Immune cells' backup mechanism revealed

The enzyme TBK1 is an important component of the innate immune system that plays a critical role in the defence against viruses. Upon mutation-induced loss of TBK1 function, patients show an increased susceptibility to viral infections. But if TBK1 is not expressed at all, this clinical effect is not seen.

In the human body, viral particles are recognised by pattern recognition receptors (PRRs) situated within the cell or on the cell surface. Upon activation a signalling cascade is initialised, which ultimately results in the production and release of signalling molecules such as interferons and cytokines. These messenger molecules alert neighbouring immune cells and point out the viral infection, inducing an immune reaction.

Part of this signalling cascade is the TANK Binding Kinase 1 (TBK1). If viral particles are detected by PRRs, TBK1 is activated. TBK1 in turn activates two transcription factors which travel into the nucleus where they induce the transcription of interferon and cytokine genes.

Point-mutations in the TBK1 gene may induce a loss of function of TBK1, which in humans manifests as clinical susceptibility to viral infections. But this effect is not observed if TBK1 is not expressed and entirely lacking in the cell. So why is a complete loss of TBK1 expression better tolerated in terms of immunocompetence than a mutation of TBK1 affecting the kinase function? Researchers from the University Hospital Bonn and the University of Bonn have published their explanation in the journal Frontiers in Immunology.

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

Just like TBK1, IKKepsilon acts downstream of PRRs and controls the expression of interferons. The two proteins are also very similar in structure, with more than 60% sequence homology. A novel finding is that TBK1 has a direct effect on IKKepsilon; Wegner noted, “In myeloid cells, we could show that TBK1 regulates the expression of the related kinase IKKepsilon.”

TBK1 reduces the stability of IKKepsilon; this process is independent of the protein’s enzymatic function. “Accordingly, TBK1 that is nonfunctional due to point mutation is still able to destabilise IKKepsilon,” said Bonn’s Professor Gunther Hartmann. “This leads to a continuous degradation of the kinase IKKepsilon in human immune cells.”

Therefore, loss of TBK1 expression leads to an increased abundance of IKKepsilon. This mechanism ensures that an antiviral immune response can occur despite the absence of TBK1. Loss of function of TBK1 induced by point mutations, on the other hand, does not prevent destabilisation and degradation of IKKepsilon, so that ultimately both factors are not available for viral defence. Increased susceptibility to viral infections is the result.

In a healthy organism, increased amounts of IKKepsilon can thus compensate for the loss of TBK1. This becomes particularly important when viruses specifically seek to eliminate the body’s own defences. Herpes, HIV and even SARS-CoV-2 are able to specifically induce TBK1 degradation. Also, several bacterial species are capable of causing the degradation of TBK1.

“Our data clearly show that human immune cells have an important backup mechanism,” Wegner said. “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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