Fusion of protein aggregates facilitates asymmetric damage segregation.

Peter Walter,Miguel Coelho,Thilo Gross,Simon Alberti,Steven J Lade,Iva M Tolić

doi:10.1371/journal.pbio.1001886

Abstract

Author SummaryDuring their lifetime, cells accumulate damage that is inherited by the daughter cells when the mother cell divides. The amount of inherited damage determines how long the daughter cell will live and how fast it will age. We have discovered fusion of protein aggregates as a new strategy that cells use to apportion damage asymmetrically during division. By combining live-cell imaging with a mathematical model, we show that fission yeast cells divide the damage equally between the two daughter cells, but only as long as the amount of damage is low and harmless. However, when the cells are stressed and the damage accumulates to higher levels, the aggregated proteins fuse into a single clump, which is then inherited by one daughter cell, while the other cell is born clean. This form of damage control may be a universal survival strategy for a range of cell types, including stem cells, germ cells, and cancer cells.

Highlights

A dividing cell can deal with damaged material in two different ways
While the lower disaggregase activity of Hsp104 from S. pombe, when compared to its S. cerevisiae homolog [6], likely accounts for the presence of aggregates under favorable conditions, deleting hsp104 resulted in increased aggregation (Figure S1F–I) and increased cell death after stress [6], while labeling the endogenous Hsp104 with GFP has no effect on stress recovery [6]
We show that fusion of aggregated proteins into a single large unit is sufficient to establish asymmetric segregation of damage, thereby generating a cell clean of aggregates

Summary

Introduction

A dividing cell can deal with damaged material in two different ways. First, the damaged material can be segregated asymmetrically during division, such that it is concentrated in one of the two newborn daughter cells, while the other cell is born clean. In phases of rapid growth, damaged material can be segregated randomly, leading to less asymmetric segregation of damage between daughters In this case, accumulation of damage within any cell is prevented by rapid divisions that dilute the damaged material. Protein aggregates are a type of damaged material, composed of insoluble and dense protein particles [1] These aggregates, instead of being degraded, accumulate in the cell during stress and aging [2,3,4]. To deal with protein aggregates during cell division, Escherichia coli and Saccharomyces cerevisiae, as well as stem cells, use asymmetric segregation, where aggregates are retained by one cell, generating a clean sister cell [2,3,7,8,9,10]. The mechanisms underlying aggregate segregation in eukaryotic cells that divide symmetrically are unclear

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