Protein aggregates are associated with replicative aging without compromising protein quality control

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.DOI: http://dx.doi.org/10.7554/eLife.06197.001

Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel–Lindau tumor suppressor protein

“…Even under normal growth conditions, fission yeast cells exhibited Hsp104-positive dots, as seen in budding yeast (Saarikangas and Barral, 2015). Upon pVHL overexpression, large Hsp104-positive pVHL inclusions were located either at the cell ends or close to, but clearly outside of, the nucleus, in contrast with the recent observations in budding yeast (Miller et al, 2015).…”

Role of sHsps in organizing cytosolic protein aggregation and disaggregation

“…The coaggregation of sHsps with misfolded proteins is employed to actively sequester substrates and promotes their deposition in large cellular assemblies (Escusa-Toret et al 2013;Miller et al 2015b;Saarikangas and Barral 2015;Shiber et al 2013;Song et al 2014;Specht et al 2011). This concept is changing our view on protein aggregation, which so far was described as an uncontrolled disastrous process resulting from proteostasis collapse only.…”

“…Moreover, apart from IPOD and INQ (JUNQ), additional stress-induced aggregates were described to exist in the yeast cytosol. These deposits were referred to as peripheral aggregates (Specht et al 2011), stress foci (Song et al 2014;Spokoini et al 2012), Q-bodies (Escusa-Toret et al 2013), or APOD (Saarikangas and Barral 2015). As all of these aggregates reside in the cytosol and depend on Hsp42 for formation, we simplify the currently non-uniform nomenclature in this review and refer to them as CytoQ (cytosolic quality control compartment) (Miller et al 2015a).…”

“…It harbors a nuclear localization sequence and upon stress treatment, a major fraction of cellular Btn2 colocalizes with INQ (Malinovska et al 2012;Miller et al 2015a). The constitutively expressed sHsp Hsp42 is required for CytoQ formation at physiological heat-stressed conditions (e.g., 38°C) (EscusaToret et al 2013;Malinovska et al 2012;Miller et al 2015a;Saarikangas and Barral 2015;Shiber et al 2013;Song et al 2014;Specht et al 2011). Hsp42 is excluded from the nucleus, explaining its compartment-specific function in misfolded protein sequestration in the cytosol and its exclusive colocalization with CytoQ (Malinovska et al 2012;Specht et al 2011).…”

“…Here, partial aggregation of the reporters can be observed, in contrast to hsp42Δ cells. The dependence on Hsp42 for protein aggregation can thus be at least partially overcome by inhibiting aggregate solubilization (Escusa-Toret et al 2013;Saarikangas and Barral 2015). The aggregate coalescence activity of Hsp42 was demonstrated by re-addition of Hsp42 to hsp42Δ hsp104Δ cells harboring multiple small aggregates, causing aggregate fusion to a single focus (Saarikangas and Barral 2015).…”