Active Cells, Biochemistry & Physiology Genetics & Molecular Biology

Cleave-to-modify: exploring proteolytic processing in Ubl-fusion proteins

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

A protein called SDE2 gets snipped in half by a cellular enzyme, and the freed fragment may go on to tag other proteins—a process that looks a lot like the well-known ubiquitin system for marking proteins for destruction. This matters because most of the hundreds of proteins that contain a ubiquitin-like (Ubl) domain have never been tested for this kind of cleavage. The ubiquitin system itself was discovered decades ago and is now known to control everything from cell division to immune responses. If other Ubl-fusion proteins are also cleaved, the cell may have a whole hidden layer of regulation that scientists have simply missed. The project is fundamental science—it asks a basic question about how cells work, with no immediate practical application. But similar curiosity-driven work on ubiquitin led directly to cancer therapies and drugs for neurodegenerative disease. If the Maniaci lab finds that many Ubl-fusion proteins are cleaved and their fragments act as signals, it could open an entirely new branch of cell biology, with future implications for understanding disease and designing drugs that tweak those signals.

View original technical description
The life cycle of proteins, from synthesis to modification and degradation, is controlled by a wide range of cellular processes. Classically, the ubiquitin- proteasome system tags the small ubiquitin protein onto targets to signal for their degradation. Ubiquitin shares its folding structure with ubiquitin-like (Ubl) proteins, a diverse family of proteins. Ubl-fusion proteins are larger proteins containing within them a ubiquitin-like domain, the implications of which are poorly understood and under-studied. Maniaci lab has recently uncovered the mechanisms for SDE2, a Ubl-fusion protein which undergoes enzymatic cleavage of the Ubl-domain from the wider protein. With this project I aim to uncover other Ubl-fusion proteins which undergo similar cleavage events by using a range of chemical and cell biology techniques. Candidate proteins will be assessed for cleavage by cloning of an over-expression system in mammalian cells. Where processing is observed, these reactions will be explored using lysate fractionation screening and proteomics to identify the interactors and enzymes responsible. Tools will be developed to study the fate of cleaved Ubl-domains, exploring the possibility of substrate conjugation similar to other Ubls. This study will provide great insight into the Ubl- fusion class of proteins, with the potential to discover vital new pathways in cellular regulation.

View the original record at the funder ↗

Researchers

Callum Stanton (EPMC Awardee)

Related Research

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Original classification

PhD Studentship (Basic)

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