Friday, May 29, 2009

Newly Discovered Analog complexity in a Genetic Signal

I've written before about the cell's complex analog computing network, both phospho-activating enzymes, and gene activation. In a very recent pre-publication paper we have a specific example of just how complex this type of network can be. One type of protein called signal transducer and activator of transcriptionA1 (STAT) proteins are parts of the network that lie in a short path between extra-cellular signaling and nuclear gene activation primarily involved in the development and function of the immune system, playing a role in maintaining immune tolerance and surveillance for tumors and other cellular errors.

Cheon, H., & Stark, G. (2009). Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0903487106

The thrust of this paper4 is that one particular member of the STAT family, STAT1, acts as a transcription factor (TF) in both the unphosphorylated state and the phosphorylated. It had long been known that it works as a TF when phosphorylated, as a result of the activity of specific cytokines, accumulating in the nucleus. A few years ago it was demonstrated that the unphosphorylated version of STAT1, U-STAT1, moves in and out of the nucleus via a different mechanism than that which ships the phosphorylated version into the nucleus.2

Figure 1: A model of Stat1 nucleocytoplasmic shuttling. Click on image to see original caption. (From Ref 2, Figure 10.)

(See The Nuclear Pore Complex for a summary of how things are moved in and out of the nucleus.

The phosphorylated STAT1, (P-STAT1), forms a dimer (either with itself, a homodimer, or with phosphorylated STAT3, a heterodimer) and is shipped into the nucleus. Once in the nucleus, it binds to specific DNA sequences (called Interferon-Gamma Activated Sequences: GAS's) as part of transcription activation. When it releases from the DNA it becomes eligible for dephosphorylation, joining the shuttling of U-STAT1 between the nucleoplasm and the cytoplasm.

It was recently "also recognized that cytokine stimulation triggers nuclear retention of dimeric STATs, rather than affecting the rate of nuclear import."1

Figure 2: STATs at the nuclear envelope. (From Ref 1, figure 2.)

What this new paper does is to show the much greater complexity of the STAT1 signal than we expected. A number of genes appear to see increased expression as a result of enhanced U-STAT1 in the nucleus. This was demonstrated by increasing its concentration:
exogenously in the absence of IFN [interferon, the specific type of cytokine involved] treatment. In response, the expression of many immune regulatory genes (e.g., IFI27, IFI44, OAS, and BST2) was increased. In human fibroblasts or mammary epithelial cells treated with low concentrations of IFN-β or IFN-γ, the expression of the same genes increased after 6 h and continued to increase after 48 or 72 h, long after the concentration of YP-STAT1 had returned to basal levels. Consistent with its activity as a transcription factor, most U-STAT1 was present in the nuclei of these cells before IFN treatment, and the fraction in nuclei increased 48 h after treatment with IFN. We conclude that the nuclear U-STAT1 that accumulates in response to IFNs maintains or increases the expression of a subset of IFN-induced genes independently of YP-STAT1, and that many of the induced proteins are involved in immune regulation.

Another discovery reported in this paper is that YP-STAT1 actually enhances the expression of STAT1. Also, "[i]n addition to the rapid activation of STAT1 gene expression in response to YP-STAT1, the STAT1 gene is also induced by U-STAT1." In other words, to some extent even the unphosphorylated version of STAT1 tends to induce its own expression.

All of this activity is dependent on cell type, and probably also on the specific state of the cell. In other words, this is not an isolated "cascade", but part of a large and sophisticated computation network, using analog concentration signals and several feedback loops to control the expression of more than 100 genes involved with the immune response.

This constitutes a specific example of how the cell performs the extremely complex calculation needed to determine its specific behavior as part of a complex body facing a variety of complex challenges that must be responded to for survival.


A1 "signal transducer and activator of transcription (STAT) proteins"

The Wiki Articles on STAT and STAT1 have not yet been updated with this information, as of this writing. Presumably that will change before this post becomes stale.


1. Nucleocytoplasmic shuttling of STAT transcription factors

2. Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1

3. Green fluorescent protein-tagging reduces the nucleocytoplasmic shuttling specifically of unphosphorylated STAT1

4. Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes

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