Limits...
Fusion of protein aggregates facilitates asymmetric damage segregation.

Coelho M, Lade SJ, Alberti S, Gross T, Tolić IM - PLoS Biol. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, United States of America.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

A stochastic model for aggregate dynamics and segregation at cell division.(A) The model. Smallest size aggregates (gray) are generated (gen) and fuse, resulting in nucleation (nuc) of an aggregate of size ≥ ν (green, ν = visibility threshold), fusion events (fus) between aggregates of size ≥ ν, and growth (gro) of an aggregate of size ≥ ν due to fusion with an aggregate of size < ν. Aggregates are randomly assigned to one of the two new compartments at division. (B) Aggregate size distribution (a.u.) averaged across the cell population. Aggregate amount from the experiment was compared with aggregate sizes from the model by scaling, with a scaling parameter I0 (Figure S3A). (C) Number of fusion events per cell cycle versus number of aggregates at birth, in model and experiment (see labels). (D) Nucleation events per cell cycle as a function of the number of aggregates at birth, in model and experiment (see labels). (E) Segregation asymmetry of aggregate number versus the total number of aggregates at division (see text). The scheme on the left represents different modes of segregation. The data are mean ± SEM from >3 independent experiments. See also Figure S3.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061010&req=5

pbio-1001886-g002: A stochastic model for aggregate dynamics and segregation at cell division.(A) The model. Smallest size aggregates (gray) are generated (gen) and fuse, resulting in nucleation (nuc) of an aggregate of size ≥ ν (green, ν = visibility threshold), fusion events (fus) between aggregates of size ≥ ν, and growth (gro) of an aggregate of size ≥ ν due to fusion with an aggregate of size < ν. Aggregates are randomly assigned to one of the two new compartments at division. (B) Aggregate size distribution (a.u.) averaged across the cell population. Aggregate amount from the experiment was compared with aggregate sizes from the model by scaling, with a scaling parameter I0 (Figure S3A). (C) Number of fusion events per cell cycle versus number of aggregates at birth, in model and experiment (see labels). (D) Nucleation events per cell cycle as a function of the number of aggregates at birth, in model and experiment (see labels). (E) Segregation asymmetry of aggregate number versus the total number of aggregates at division (see text). The scheme on the left represents different modes of segregation. The data are mean ± SEM from >3 independent experiments. See also Figure S3.

Mentions: Based on our experimental observations, we developed a stochastic aggregation model (Figure 2A) that allows for the simulation of aggregate size distributions (Figure 2B), which can be compared with the experimentally observed size distributions (measured by the intensity of Hsp104-GFP in each puncta, a.u.). A key feature distinguishing the proposed model from other models [18]–[20] is that aggregate segregation asymmetry is an output rather than an input of our model.


Fusion of protein aggregates facilitates asymmetric damage segregation.

Coelho M, Lade SJ, Alberti S, Gross T, Tolić IM - PLoS Biol. (2014)

A stochastic model for aggregate dynamics and segregation at cell division.(A) The model. Smallest size aggregates (gray) are generated (gen) and fuse, resulting in nucleation (nuc) of an aggregate of size ≥ ν (green, ν = visibility threshold), fusion events (fus) between aggregates of size ≥ ν, and growth (gro) of an aggregate of size ≥ ν due to fusion with an aggregate of size < ν. Aggregates are randomly assigned to one of the two new compartments at division. (B) Aggregate size distribution (a.u.) averaged across the cell population. Aggregate amount from the experiment was compared with aggregate sizes from the model by scaling, with a scaling parameter I0 (Figure S3A). (C) Number of fusion events per cell cycle versus number of aggregates at birth, in model and experiment (see labels). (D) Nucleation events per cell cycle as a function of the number of aggregates at birth, in model and experiment (see labels). (E) Segregation asymmetry of aggregate number versus the total number of aggregates at division (see text). The scheme on the left represents different modes of segregation. The data are mean ± SEM from >3 independent experiments. See also Figure S3.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061010&req=5

pbio-1001886-g002: A stochastic model for aggregate dynamics and segregation at cell division.(A) The model. Smallest size aggregates (gray) are generated (gen) and fuse, resulting in nucleation (nuc) of an aggregate of size ≥ ν (green, ν = visibility threshold), fusion events (fus) between aggregates of size ≥ ν, and growth (gro) of an aggregate of size ≥ ν due to fusion with an aggregate of size < ν. Aggregates are randomly assigned to one of the two new compartments at division. (B) Aggregate size distribution (a.u.) averaged across the cell population. Aggregate amount from the experiment was compared with aggregate sizes from the model by scaling, with a scaling parameter I0 (Figure S3A). (C) Number of fusion events per cell cycle versus number of aggregates at birth, in model and experiment (see labels). (D) Nucleation events per cell cycle as a function of the number of aggregates at birth, in model and experiment (see labels). (E) Segregation asymmetry of aggregate number versus the total number of aggregates at division (see text). The scheme on the left represents different modes of segregation. The data are mean ± SEM from >3 independent experiments. See also Figure S3.
Mentions: Based on our experimental observations, we developed a stochastic aggregation model (Figure 2A) that allows for the simulation of aggregate size distributions (Figure 2B), which can be compared with the experimentally observed size distributions (measured by the intensity of Hsp104-GFP in each puncta, a.u.). A key feature distinguishing the proposed model from other models [18]–[20] is that aggregate segregation asymmetry is an output rather than an input of our model.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus