## NFκB

NF$\kappa$B is a transcription factor, i.e. a protein which can bind to DNA and cause a particular gene to be read more or less often. This means that more or less of a certain protein is produced and this changes the behaviour of the cell. The full name of this transcription factor is ‘nuclear factor, $\kappa$-light chain enhancer of B cells’. The term ‘nuclear factor’ is clear. The substance is a transcription factor and to bind to DNA it has to enter the nucleus. NF$\kappa$B is found in a wide variety of different cells and its association with B cells is purely historical. It was found in the lab of David Baltimore during studies of the way in which B cells are activated. It remains to explain the $\kappa$. B cells produce antibodies each of which consists of two symmetrical halves. Each half consists of a light and a heavy chain. The light chain comes in two variants called $\kappa$ and $\lambda$. The choice which of these a cell uses seems to be fairly random. The work in the Baltimore lab had found out that NF$\kappa$B could skew the ratio. I found a video by Baltimore from 2001 about NF$\kappa$B. This is probably quite out of date by now but it contained one thing which I found interesting. Under certain circumstances it can happen that a constant stimulus causing activation of NF$\kappa$B leads to oscillations in the concentration. In the video the speaker mentions ‘odd oscillations’ and comments ‘but that’s for mathematicians to enjoy themselves’. It seems that he did not believe these oscillations to be biologically important. There are reasons to believe that they might be important and I will try to explain why. At the very least it will allow me to enjoy myself.

Let me explain the usual story about how NF$\kappa$B is activated. There are lots of animated videos on Youtube illustrating this but I prefer a description in words. Normally NF$\kappa$B is found in the cytosol bound to an inhibitor I$\kappa$B. Under certain circumstances a complex of proteins called IKK forms. The last K stands for kinase and IKK phosphorylates I$\kappa$B. This causes I$\kappa$B to be ubiquinated and thus marked for degradation (cf. the discussion of ubiquitin here). When it has been destroyed NF$\kappa$B is liberated, moves to the nucleus and binds to DNA. What are the circumstances mentioned above? There are many alternatives. For instance TNF$\alpha$ binds to its receptor, or something stimulates a toll-like receptor. The details are not important here. What is important is that there are many different signals which can lead to the activation of NF$\kappa$B. What genes does NF$\kappa$B bind to when it is activated? Here again there are many possibilities. Thus there is a kind of bow tie configuration where there are many inputs and many outputs which are connected to a single channel of communication. So how is it possible to arrange that when one input is applied, e.g. TNF$\alpha$ the right genes are switched on while another input activates other genes through the same mediator NF$\kappa$B? One possibility is cross-talk, i.e. that this signalling pathway interacts with others. If this cannot account for all the specificity then the remaining possibility is that information is encoded in the signal passing through NF$\kappa$B itself. For example, one stimulus could produce a constant response while another causes an oscillatory one. Or two stimuli could cause oscillatory responses with different frequencies. Evidently the presence of oscillations in the concentration of NF$\kappa$B presents an opportunity for encoding more information than would otherwise be possible. To what extent this really happens is something where I do not have an overview at the moment. I want to learn more. In any case, oscillations have been observed in the NF$\kappa$B system. The primary thing which has been observed to oscillate is the concentration of NF$\kappa$B in the nucleus. This oscillation is a consequence of the movement of the protein between the cytosol and the nucleus. There are various mathematical models for describing these oscillations. As usual in modelling phenomena in cell biology there are models which are very big and complicated. I find it particularly interesting when some of the observations can be explained by a simple model. This is the case for NF$\kappa$B where a three-dimensional model and an explanation of its relations to the more complicated models can be found in a paper by Krishna, Jensen and Sneppen (PNAS 103, 10840). In the three-dimensional model the unknowns are the concentrations of NF$\kappa$B in the nucleus, I$\kappa$B in the cytoplasm and mRNA coding for I$\kappa$B. The oscillations in normal cells are damped but sustained oscillations can be seen in mutated cells or corresponding models.

What is the function of NF$\kappa$B? The short answer is that it has many. On a broad level of description it plays a central role in the phenomenon of inflammation. In particular it leads to production of the cytokine IL-17 which in turn, among other things, stimulates the production of anti-microbial peptides. When these things are absent it leads to a serious immunodeficiency. In one variant of this there is a mutation in the gene coding for NEMO, which is one of the proteins making up IKK. A complete absence of NEMO is fatal before birth but people with a less severe mutation in the gene do occur. There are symptoms due to things which took place during the development of the embryo and also immunological problems, such as the inability to deal with certain bacteria. The gene for NEMO is on the X chromosome so that this disease is usually limited to boys. More details can be found in the book of Geha and Notarangelo mentioned in  a previous post.