Abstract
Cellular membranes are important biological interfaces. Not only do they compartmentalise cells from the environment and organelles from each other, but they also act as signalling platforms. Membrane proteases mediate many of their functions and are primary triggers of signalling. Rhomboids, which are intramembrane serine proteases, are a relatively recently discovered family of membrane proteases that control both signalling and membrane quality control. Rhomboid proteases are members of a much wider rhomboid-like superfamily, most of which are pseudoproteases, having lost their proteolytic activity. The bottleneck in understanding the biological role of rhomboid proteases is identifying their substrates. This has proved to be a difficult problem with all proteases and there is no single definitive approach. We have now successfully developed a combined bioinformatic and experimental pipeline to reveal the substrates of mammalian rhomboids. This has led us to uncover a role for rhomboids in controlling calcium signalling and I shall discuss this novel mechanism of signalling homeostasis, as well as its physiological consequences in human cells.
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