Overexpression of a yeast prion protein prevents cells from undergoing mitosis by sequestering a key spindle pole body component, Treusch and Lindquist report.
The prion Rnq1 can adopt a self-perpetuating, amyloid conformation called [RNQ+]. This conformation enables toxicity in cells overexpressing the protein. Misfolded Rnq1 molecules assemble into large, insoluble amyloid fibers, but these structures actually protect cells by removing from the cytoplasm smaller, soluble [RNQ+] oligomers that are thought to cause cell death. How these smaller, amorphous aggregates harm cells is unclear, however.
Treusch and Lindquist found that yeast overexpressing Rnq1 in the presence of [RNQ+] arrested in mitosis. The cells failed to duplicate their spindle pole bodies (SPBs, the yeast equivalent of centrosomes) and therefore formed monopolar spindles that activated the spindle assembly checkpoint. The researchers analyzed several SPB proteins and found that Spc42, a core component required for SPB duplication, was sequestered into cytoplasmic [RNQ+] aggregates. Modestly increasing Spc42 levels was sufficient to restore normal growth to Rnq1-overexpressing yeast.
Though Rnq1 isn't normally involved in SPB duplication, the results demonstrate that misfolded proteins can cause toxicity through specific interactions with other proteins, rather than through general inhibition of the cell's protein folding and degradation machinery. Similarly specific interactions could underlie the toxicity associated with protein aggregates in human diseases like Huntington's and amyotrophic lateral sclerosis.