Misfolded proteins are toxic to cells and disrupt normal cellular functions, causing age-related degenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s. A new study from Stanford University, led by researchers in Judith Frydman’s lab, has discovered a previously unknown cellular pathway for clearing misfolded proteins from the nucleus. The study integrated genetic, imaging, and biochemical approaches to understand how yeast cells dealt with misfolded proteins.
For their work, published in Nature Cell Biology, the team found that the nucleus and cytoplasm have a shared ‘garbage dump’ site for misfolded proteins located in the intersection of the nucleus and vacuole. After being moved to the ‘garbage dump’ site, the misfolded proteins are then relocated inside the vacuole for degradation.
Cells can deal with misfolded proteins by refolding them, eliminating them, or storing them at a specific cellular location. The cellular machinery forms small misfolded-protein inclusions in different places within the nucleus and cytoplasm, like tiny garbage dumps, that then migrate toward the boundary between the nucleus and the vacuole, a bigger garbage dump.
Eventually, the nuclear and cytoplasmic misfolded protein inclusions line up to face each other, with the nuclear envelope separating them. The communication back and forth between the nucleus and the cytoplasm was not something the team expected.
Yeasts’ vacuole is similar to mammalian cells’ lysosome, and the team suspected that the inclusions were being sent to the vacuole for degradation. The scientists found that the cytoplasmic inclusions were being pushed into the vacuole as expected. However, the route for nuclear inclusions went straight from the nucleus into the vacuole at the junction of these two membranes.
The team showed that ESCRT II/III and Vps4 proteins facilitated that budding-into-the-vacuole action, which are proteins that form small vesicles for molecular transport.
“Tying that particular family of proteins and this aspect of vesicle traffic biology to protein clearance gives us a new way to look at Alzheimer’s, Parkinson’s, Huntington’s – all these neurodegenerative diseases,” says study co-lead author Emily Sontag.