Cells rely on a protein-cutting enzyme called the signal peptidase complex (SPC) to snip specific proteins loose from membrane compartments, releasing fragments that travel to the nucleus to switch genes on or off—and the researcher has just discovered that SPC does this far more often than textbooks describe. This matters because faulty cell signalling underlies diseases from cancer to Alzheimer’s, yet one major signalling route—the one SPC controls—remains largely unexplored in mammals. The standard view holds that SPC only trims signal peptides from newly made proteins entering the endoplasmic reticulum. The researcher’s preliminary work shows SPC also liberates membrane-bound transcription regulators, and that this is likely not a one-off: multiple similar targets probably exist in the human genome. Viruses such as Zika and Dengue already hijack SPC to replicate, making the enzyme a potential weak point in infection. If successful, this fundamental science will map how common SPC-driven signalling is, how the cell controls it, and how viruses exploit it. There is no immediate clinical application, but understanding a previously hidden communication channel between the ER and nucleus could eventually reveal new targets for drugs against viral infections or diseases where gene regulation goes awry.
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Cells are the building blocks of all living organisms and need to communicate with each other and within themselves to maintain the body's proper functioning. This communication is vital for coordinating the activities of different cells and tissues, ensuring good health, and helping the body respond to changes in its surroundings. Cells send messages using molecules like proteins, and when this communication breaks down, it can cause diseases. For example, faulty signals can make cells grow uncontrollably leading to tumours, or in Alzheimer's disease, neurons lose their ability to communicate, leading to memory and cognitive issues. So, understanding how cells communicate and what goes wrong in diseases is very important for medicine. Among the many ways cells send signals, one under-studied method involves cutting specific proteins that reside within the various membrane compartments of cells. This process releases a part of the protein that then moves into the cell's nucleus, where it can turn genes on/off, triggering biological responses. Although we don’t know as much about this pathway compared to others, there's growing evidence that problems with this kind of signalling can lead to various diseases. This form of communication happens in all living organisms, but only a few examples have been found in mammals so far—though there are likely many more to discover. The starting point for this research is my recent discovery of a surprising new role for a membrane protease (a type of enzyme) called the signal peptidase complex (SPC). Until now, textbooks describe SPC as responsible for removing signal peptides from proteins as they enter the endoplasmic reticulum (ER), a cell structure. Recently, it was also found that viruses like Zika and Dengue use SPC to help them reproduce. However, I discovered that SPC has an entirely unexpected role in releasing a membrane-bound transcription regulator from the ER, a process that leads to changes in gene activity. Coupled with other recent work, it is now clear that SPC has a broader function than previously thought. Preliminary evidence suggests that my earlier discovery is not unique, and that there are multiple other SPC-cleaved membrane-bound transcriptional regulators in the human genome, and its known role in viruses infection makes it even more important to study. In this proposal, I aim to find out (i) how common this new role of SPC in processing membrane-bound transcription regulators is, (ii) how SPC's cutting of membrane proteins is controlled, and (iii) how viruses take advantage of this function during infection. Overall, this research will provide a new perspective on SPC's role, expand our understanding of membrane-bound transcription regulators, and uncover new signalling pathways between the ER and the nucleus that underline important biological processes in health and disease.
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