Aggresome-Like Formation Promotes Resistance to Proteotoxicity in Cells from Long-Lived Species

Abstract

The capacity of cells to maintain proteostasis declines with age, causing rapid accumulation of damaged proteins and protein aggregates, which plays an important role in age-related disease etiology. While our group and others have identified that proteostasis is enhanced in long-lived species, there are no data on whether this leads to better resistance to proteotoxicity. We compared the sensitivity of cells from long- (naked mole rat [NMR]) and short- (Mouse) lived species to proteotoxicity, by measuring the survival of fibroblasts under polyglutamine (polyQ) toxicity, a well-established model of protein aggregation. Additionally, to evaluate the contribution of proteostatic mechanisms to proteotoxicity resistance, we down-regulated a key protein of each mechanism (autophagy—ATG5; ubiquitin-proteasome—PSMD14; and chaperones—HSP27) in NMR fibroblasts. Furthermore, we analyzed the formation and subcellular localization of inclusions in long- and short-lived species. Here, we show that fibroblasts from long-lived species are more resistant to proteotoxicity than their short-lived counterparts. Surprisingly, this does not occur because the NMR cells have less polyQ82 protein aggregates, but rather they have an enhanced capacity to handle misfolded proteins and form protective perinuclear and aggresome-like inclusions. All three proteostatic mechanisms contribute to this resistance to polyQ toxicity but autophagy has the greatest effect. Overall, our data suggest that the resistance to proteotoxicity observed in long-lived species is not due to a lower level of protein aggregates but rather to enhanced handling of the protein aggregates through the formation of aggresome-like inclusions, a well-recognized protective mechanism against proteotoxicty.

The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

“…However, if there are irregularities in folding, incompletely folded, or unfolded proteins that accumulate can cause ER stress, provoking UPR as a protective mechanism [44][45][46]. The formation of a dynamic structure called aggresomes is another form of protection that excludes the potentially toxic aggregates from the bulk of the cytosol [47,48]. These aggresomes/inclusion bodies are often in close proximity to the lipid droplets [49].…”

HspB1 Overexpression Improves Life Span and Stress Resistance in an Invertebrate Model

“…It is possible that this repeat enhances NMR HspB1’s ability to form oligomers, resulting in the puncta seen in both the NMR primary cells and transgenic worm line. Enhanced oligomeric activity could play a role in forming the protective aggresomes that have been observed to protect the cells of long-lived species from toxic aggregation-prone proteins ( 27 ). Whether NMR HspB1 confers special protection beyond other species’ and, if so, what features contribute to this, is an area of ongoing research in our lab.…”

Adult fibroblasts use aggresomes only in distinct cell-states

“…Additionally, many cell types form an aggresome, a structure comprised of proteins destined for degradation being trafficked along microtubules by dynein and other adapter proteins to the centrosome within a cage comprised of the intermediate filament vimentin (Johnston, Ward et al 1998, Kopito 2000, Johnston, Illing et al 2002, Iwata, Riley et al 2005, Olzmann, Li et al 2008. It is thought that aggresome formation is cytoprotective by increasing the efficiency of protein degradation by bringing together proteins destined for degradation with protein degradation machineries and organizing damaged or misfolded proteins so they do not interfere with other cellular processes (Tanaka, Kim et al 2004, Olzmann, Li et al 2008, Morrow, Porter et al 2020, Sunchu, Riordan et al 2020.…”

“…1A) (Johnston, Ward et al 1998, Kopito 2000, Johnston, Illing et al 2002, Iwata, Riley et al 2005, Olzmann, Li et al 2008). It is thought that aggresome formation is cytoprotective by increasing the efficiency of protein degradation by bringing together proteins destined for degradation with protein degradation machineries and organizing damaged or misfolded proteins so they do not interfere with other cellular processes (Tanaka, Kim et al 2004, Olzmann, Li et al 2008, Morrow, Porter et al 2020, Sunchu, Riordan et al 2020).…”