coelho2014fusion
Fusion of protein aggregates facilitates asymmetric damage segregation
Miguel Coelho, Steven J. Lade, Simon Alberti, Thilo Gross and Iva M. Tolić
PLoS Biol 12, e1001886, 2014
Asymmetric segregation of damaged proteins at cell division generates a cell that retains damage and a clean cell that supports population survival. In cells that divide asymmetrically, such as Saccharomyces cerevisiae, segregation of damaged proteins is achieved by retention and active transport. We have previously shown that in the symmetrically dividing Schizosaccharomyces pombe there is a transition between symmetric and asymmetric segregation of damaged proteins. Yet how this transition and generation of damage-free cells are achieved remained unknown. Here, by combining in vivo imaging of Hsp104-associated aggregates, a form of damage, with mathematical modeling, we find that fusion of protein aggregates facilitates asymmetric segregation. Our model predicts that, after stress, the increased number of aggregates fuse into a single large unit, which is inherited asymmetrically by one daughter cell, whereas the other one is born clean. We experimentally confirmed that fusion increases segregation asymmetry, for a range of stresses, and identified Hsp16 as a fusion factor. Our work shows that fusion of protein aggregates promotes the formation of damage-free cells. Fusion of cellular factors may represent a general mechanism for their asymmetric segregation at division.
(A) Aggregate segregation after stress (Hsp104-GFP, see labels). Thin lines encircle cells; scale bar, 1 µm. (B) Aggregate nucleation and fusion during the first cell cycle after stress. (C, Left) Three distinct optimal segregation regimes (1–3) that maximize the number of surviving cells depending on the aggregate amount in the mother cell at division (a): (1) any segregation asymmetry when the total aggregate amount is below the death threshold (d), (2) low segregation asymmetry when the amount is between d and 2d, and (3) high asymmetry when the amount is above 2d. Black lines represent pedigree lineage, and the rough cell edge represents cell death (cell lysis and shrinkage, followed by absence of growth). (Right) Aggregate amount asymmetry (absolute difference in the amount between sister cells at birth) under favorable conditions (“Control”) and at division 2 after stress.
Figure 1: (A) Aggregate segregation after stress (Hsp104-GFP, see labels). Thin lines encircle cells; scale bar, 1 µm. (B) Aggregate nucleation and fusion during the first cell cycle after stress. (C, Left) Three distinct optimal segregation regimes (1–3) that maximize the number of surviving cells depending on the aggregate amount in the mother cell at division (a): (1) any segregation asymmetry when the total aggregate amount is below the death threshold (d), (2) low segregation asymmetry when the amount is between d and 2d, and (3) high asymmetry when the amount is above 2d. Black lines represent pedigree lineage, and the rough cell edge represents cell death (cell lysis and shrinkage, followed by absence of growth). (Right) Aggregate amount asymmetry (absolute difference in the amount between sister cells at birth) under favorable conditions (“Control”) and at division 2 after stress.