Abstract
Differentiation of cellular lineages is facilitated by asymmetric segregation of fate determinants between dividing cells. In budding yeast, various aging factors segregate to the aging (mother)-lineage, with poorly understood consequences. In this study, we show that yeast mother cells form a protein aggregate during early replicative aging that is maintained as a single, asymmetrically inherited deposit over the remaining lifespan. Surprisingly, deposit formation was not associated with stress or general decline in proteostasis. Rather, the deposit-containing cells displayed enhanced degradation of cytosolic proteasome substrates and unimpaired clearance of stress-induced protein aggregates. Deposit formation was dependent on Hsp42, which collected non-random client proteins of the Hsp104/Hsp70-refolding machinery, including the prion Sup35. Importantly, loss of Hsp42 resulted in symmetric inheritance of its constituents and prolonged the lifespan of the mother cell. Together, these data suggest that protein aggregation is an early aging-associated differentiation event in yeast, having a two-faceted role in organismal fitness.
Highlights
Aging results in an increasing decline of the organism’s fitness over time (Lopez-Otin et al, 2013)
Studies on budding yeast have shown a correlation between the accumulation of protein aggregates and replicative aging by demonstrating that Hsp104mediated protein disaggregation is required for full replicative life span (Erjavec et al, 2007), and that over-expression of Mca1, which counteracts the formation of stress- and age-associated protein aggregates (Lee et al, 2010; Hill et al, 2014), extends the life span of yeast mother cells (Hill et al, 2014)
We found many cells displaying an aggregate and this portion increased in a progressive, age-dependent manner such that >80% of cells that had undergone more than 6 divisions displayed such a structure (Figure 1A,B), as previously reported (Aguilaniu et al, 2003; Erjavec et al, 2007)
Summary
Aging results in an increasing decline of the organism’s fitness over time (Lopez-Otin et al, 2013) This process segregates asymmetrically during budding yeast division: the mother cell forms an aging lineage, whereas the daughters generated by these mothers rejuvenate to form eternal lineages, similar to the segregation of soma and germ lineages in metazoans. Studies on budding yeast have shown a correlation between the accumulation of protein aggregates and replicative aging by demonstrating that Hsp104mediated protein disaggregation is required for full replicative life span (Erjavec et al, 2007), and that over-expression of Mca, which counteracts the formation of stress- and age-associated protein aggregates (Lee et al, 2010; Hill et al, 2014), extends the life span of yeast mother cells (Hill et al, 2014)
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