Misfolded proteins are toxic to cells. They disrupt normal functions and cause some age-related human degenerative diseases, like Alzheimer’s, Parkinson’s, and Huntington’s diseases. Cells work constantly to eliminate misfolded proteins, but these clearance mechanisms are still poorly understood.
In a new study published April 20 in Nature Cell Biology, researchers at Stanford University discovered a previously unknown cellular pathway for clearing misfolded proteins from the nucleus, the compartment where the cell stores, transcribes, and replicates its DNA. Keeping junk away from those processes is critical to normal cellular function. The new pathway could be a target for age-related disease therapies.
To find the new pathway, researchers in the lab of Judith Frydman, the Donald Kennedy Chair in the School of Humanities and Sciences, integrated several genetic, imaging, and biochemical approaches to understand how yeast cells dealt with misfolded proteins. For the experiments, the team restricted misfolded proteins to either the nucleus or the cytoplasm – the area inside the cell but outside the nucleus. The team visually followed the fate of the misfolded proteins through live-cell imaging and super-resolution microscopy.
“The first exciting thing was that we actually found that there’s communication between the nucleus and the cytoplasm,” said Emily Sontag, the co-lead author of the paper and a former postdoctoral student in the Frydman Lab. “So they’re telling each other, ‘We both have a lot of misfolded proteins; let’s coordinate to send them here to this garbage dump so that they can be removed.’”
A) A 3D reconstruction of a yeast cell engulfing cytoplasmic misfolded proteins (purple) inside of the degradation cellular machinery, or vacuole (gray).
B) Super-resolution reconstructions showing nuclear misfolded proteins (green) being targeted to the degradation cellular machinery through the nuclear-vacuolar junction (yellow). (Image credit: Fabián Morales-Polanco)
The team identified the “garbage dump” site as the intersection of the nucleus and the vacuole – an organelle full of enzymes for degrading proteins – and showed that misfolded proteins in this “garbage dump” site are moved into the inside of the vacuole for degradation. They also showed that the pathway depends on a class of proteins used to create small vesicles for transporting molecules around cells.
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