Harvard University - Department of Molecular & Cellular Biology

AN UNUSUALLY SIMPLE SIGNAL TRANSDUCTION SYSTEM

by Richard Losick

February 10th, 2006


Authors Errett Hobbs (left) and Craig Ellermeier
In this week’s Cell, Craig Ellermeier, Errett Hobbs, Eduardo Gonzalez and Rich Losick report the discovery of an unusually simple system by which bacterial cells sense and respond to an external signal.  Cells typically respond to other cells in their environment by means of intercellular signaling systems.  Frequently, these signaling systems involve a protein signal or ligand that is exported by one cell and is recognized by a receptor located on the surface of a target cell.  The receptor binds the signaling protein and transduces the signal across the cell membrane to the inside of the cell where it sets in motion a chain of events that culminates in the activation of specific genes. Often, the chain of events is complex, involving multiple proteins, including kinases and phosphatases that phosphorylate and dephosphorylate various proteins in the signal transduction pathway. 

Ellermeier, Hobbs and Gonzalez have elucidated how cells of the bacterium Bacillus subtilis respond to a protein toxin by inducing the synthesis of an immunity protein. They discovered that the toxin does double duty as a signaling protein and that the immunity protein does double duty as a receptor. Thus, the immunity protein binds the toxin not only to neutralize it but also to induce the synthesis of more immunity protein.  How does the immunity protein accomplish this feat? The gene for the immunity protein is held silent by a repressor protein in the absence of toxin. However, when cells are exposed to the toxin/ligand, the immunity protein/receptor captures the repressor and sequesters it at the cell membrane, preventing it from reaching DNA and repressing gene expression. We made this discovery by using a fusion of the repressor to a fluorescent protein called Green Fluorescent Protein. In the microscope, the fluorescently tagged repressor could be seen to localize to the cytoplasm when the toxin/ligand was absent and to the membrane when it was present.

Thus, the entire signal transduction pathway consists of only three proteins and involves no kinases or other enzymes. Instead, regulation is mediated by the formation of a membrane-bound complex. When the toxin/ligand binds to the immunity protein/receptor from outside the cell, the surface of the receptor inside the cell captures the repressor to form a three-protein complex at the membrane. This derepresses the gene for the immunity protein and hence more immunity protein is made.

One other twist to the story is that only just enough immunity protein is made to meet the needs of the cell, no more. It turns out the repressor inhibits the expression of its own gene as well as the gene for the immunity protein. Thus, the binding of the toxin/ligand derepresses the synthesis of both immunity protein/receptor and repressor. When sufficient immunity protein has been made, free repressor is no longer bound and the excess begins to accumulate. This in turn dampens further synthesis of immunity protein (and itself). Thus, a just-in-time regulatory system ensures that enough immunity protein has been made to soak up all the toxin but no more.

Proteins with similarity to the components of the simple signal transduction pathway described in this work have not yet surfaced in the data bases. But Nature rarely solves a problem in the same way only once. It will be interesting to see whether analogous, if not homologous, pathways for responding to environmental signals emerge in other systems of gene control.

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