ABOVE: Cells engineered with fewer Gr64 receptors experience cell death via apoptosis (shown in yellow), while control cells where Gr64s were not manipulated (shown in blue) persist. IWO KUCINSKI AND ALEX MASTROGIANNOPOULOS


While combing through a list of genes that are differently expressed in Drosophila cells with and without certain ribosomal mutations, researchers in developmental biologist Eugenia Piddini’s lab at the University of Bristol stumbled upon a surprise. A cluster of genes encoding six receptors known as gustatory receptors 64 (Gr64s) was upregulated in the epithelial cells of mutant larvae, which experience cellular stress as a result of the buildup of misfolded or otherwise dysfunctional proteins. It was an “intriguing and serendipitous” find, Piddini says, as Gr64s sense sugar molecules in adult flies but had no other known functions.

Piddini and her colleagues decided to investigate further, knocking out Gr64 function in larval epithelial cells containing the stress-inducing mutations. Losing the taste receptors resulted in “a spectacular amount of death” among the stressed cells, Piddini says, hinting that the receptor cluster might somehow be involved in cellular homeostasis. Indeed, the team found that the loss of Gr64s prevented the cells from digesting aggregated proteins via autophagy compared to cells with functioning receptors.

In their typical role as taste receptors in sensory cells, Gr64s also oversee calcium flow, which is involved in protein regulation. The researchers imaged calcium influxes into the mutant cells and found less activity in Gr64-free cells compared to controls, making calcium signaling a likely candidate for how the receptors might maintain proteostasis, Piddini says.

The study is “intriguing,” says Craig Montell, a neurobiologist at the University of California, Santa Barbara, who studies gustatory receptors and was not involved with the research. He adds, however, that the authors didn’t fully connect calcium activity to protein regulation. This is also top of mind for Piddini, who says the calcium activity “is a very important unknown for the proper understanding of how this receptor functions.”

M.E. Baumgartner et al., “The Gr64 cluster of gustatory receptors promotes survival and proteostasis of epithelial cells in Drosophila,” PLOS Biol, 20:e3001710, 2022.