New tool tracks a hidden protein involved in viral infection and cell cleanup

This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Viruses such as influenza A and dengue can hijack a cellular system that helps manage protein aggregates. Previous work by FMI emeritus group leader Patrick Matthias and his team showed that a small protein called ubiquitin plays an important role in this process.

The viruses rely on a free form of ubiquitin that is not attached to other proteins. This "unanchored" ubiquitin is also involved in immune responses and protein cleanup, but it has been difficult to study because researchers lack tools that can specifically detect it. So, Matthias and collaborators at ETH Zurich set out to build a tool that could distinguish unanchored ubiquitin from other forms of the protein.

Working with researchers in Guillaume Diss's lab and the FMI structural biology facility, Longlong Wang—a former postdoc with Matthias—started with HDAC6, a protein that naturally binds unanchored ubiquitin. They improved the binding, then used computer-based protein design tools, including AlphaFold, to generate thousands of new versions. Their work is published in Science Advances.

One candidate, called UBiP10, performed especially well. When tested in the lab, it captured unanchored ubiquitin while mostly ignoring ubiquitin attached to other proteins. It could also isolate unanchored ubiquitin from human cells and influenza A virus particles.

The researchers then used UBiP10 to see where unanchored ubiquitin collects inside cells. When the proteasome—the cell's main protein-disposal system—was blocked, damaged proteins gathered into structures called aggresomes. UBiP10 showed that unanchored ubiquitin formed a layer around these structures rather than building up inside them.

This layer depended on a motor protein called myosin 10. The role of this ubiquitin-rich layer is still unclear. But UBiP10 gives researchers a new way to track a form of ubiquitin that has been difficult to study, which could help clarify its roles in viral infection and the cell's protein-cleanup systems, Matthias says.