It takes more than a village

Molecular geneticists refer to big boss proteins that switch on broad developmental or metabolic programs as “master regulators.” One such factor, the Activating Transcription Factor 6α (ATF6α) protein, takes charge following a cellular crisis known as endoplasmic reticulum (ER) stress, which is triggered by the accumulation of misfolded and aggregated proteins.

Molecularly, the ER stress emergency response is always poised for action. Inactive ATF6α is normally embedded in cellular membranes, but at the first hint of protein overload, its working end springs Supermanlike into the nucleus, binds DNA and kicks on a host of target genes whose job is to clear a protein logjam.

In their latest study, selected by the editors of the Journal of Biological Chemistry as “Paper of the Week,” a team led by Stowers Investigators Ron and Joan Conaway reveal that, unlike the real Superman, ATF6α does not work solo. They found that it takes not a village but a metropolis to activate an ATF6α target.

Researchers know that all DNA-binding factors partner with other proteins to switch genes on or off. What is remarkable here is their sheer number. “It would be very interesting to find out whether this is the norm,” says Ron Conaway, PhD, who with Joan Conaway, PhD, is co-corresponding author of the study. “This work raises a ton of interesting questions about mechanism.”

Solving these puzzles could reveal molecular targets for seemingly unrelated diseases. While a little ATF6α signaling is absolutely essential for cellular housekeeping, unrelieved ER stress is a hallmark of neurodegenerative conditions like Alzheimer’s and Huntington’s disease and is correlated with insulin insensitivity and type 2 diabetes.

The study was published in the June 29, 2012, issue of the Journal of Biological Chemistry.