Polarised Asymmetric Inheritance of Accumulated Protein Damage in Higher Eukaryotes

127

134

Aging is associated with the accumulation of several types of damage: in particular, damage to the proteome. Recent work points to a conserved replicative rejuvenation mechanism that works by preventing the inheritance of damaged and misfolded proteins by specific cells during division. Asymmetric inheritance of misfolded and aggregated proteins has been shown in bacteria and yeast, but relatively little evidence exists for a similar mechanism in mammalian cells. Here, we demonstrate, using long-term 4D imaging, that the vimentin intermediate filament establishes mitotic polarity in mammalian cell lines and mediates the asymmetric partitioning of damaged proteins. We show that mammalian JUNQ inclusion bodies containing soluble misfolded proteins are inherited asymmetrically, similarly to JUNQ qualitycontrol inclusions observed in yeast. Mammalian IPOD-like inclusion bodies, meanwhile, are not always inherited by the same cell as the JUNQ. Our study suggests that the mammalian cytoskeleton and intermediate filaments provide the physical scaffold for asymmetric inheritance of dynamic quality-control JUNQ inclusions. Mammalian IPOD inclusions containing amyloidogenic proteins are not partitioned as effectively during mitosis as their counterparts in yeast. These findings provide a valuable mechanistic basis for studying the process of asymmetric inheritance in mammalian cells, including cells potentially undergoing polar divisions, such as differentiating stem cells and cancer cells.inclusion body | spatial quality control A ging is universally associated with a global decline in cellular function (1-3). Due to the multiplicity of mechanisms that undergo aging-related dysfunction, its mechanistic basis, or "senescence factor," has been difficult to pinpoint. Several studies have provided key insight into the identities of senescence factors by studying the asymmetric segregation of damage in singlecell organisms that rejuvenate the emerging generation by preventing the inheritance of damaged factors such as DNA, lipids, and proteins (1, 4, 5). In particular, a number of seminal studies have demonstrated that bacteria and yeast use a complex and multifaceted machinery to prevent the inheritance of damaged and aggregated proteins by the new generation by restricting them to the older lineage during cell division (1,6,7).Although the precise mechanism for asymmetric inheritance of aggregates has been a matter of much debate (1, 7), the emerging model is that the spatial arrangement of misfolded proteins into quality control-associated IB (inclusion body)-like structures plays an essential role in asymmetric inheritance (1, 7). A key property of some quality-control IBs and other IBlike structures, which allows the cell to retain them in a specific lineage during mitosis, is their association and interaction with cellular organelles and cytoskeleton. In bacteria, for example, aggregated proteins are collected at the old pole of a dividing cell (5). A similar mechanism has been proposed in fission yeast (8). In the budd...

“…Asymmetric segregation of IBs was demonstrated in previous studies, in particular using HttQ119 (12) (Fig. 2D), which forms insoluble IPODs (15).…”

Section: Junqs Are Asymmetrically Segregated During Mitosis In Mammaliansupporting

confidence: 74%

Section: Significancementioning

confidence: 99%

Dynamic JUNQ inclusion bodies are asymmetrically inherited in mammalian cell lines through the asymmetric partitioning of vimentin

Ogrodnik

Salmonowicz

Brown

et al. 2014

127

134

“…We therefore refer to juxtanuclear inclusions with mobile quality control substrates as JUNQs, and the polyQ Htt inclusions as IPODs, to distinguish between these distinct types of inclusion phenotypes. In particular, there is evidence that the accumulation of Htt in an IB is protective of cell viability (10, 13), whereas cytosolic Htt that fails to be sequestered in an IB is more toxic (22). Other experiments have suggested that familial ALS (fALS)-associated mutant SOD1 is most toxic when localized to an IB (8).…”

Section: Resultsmentioning

confidence: 99%

Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

Weisberg

Lyakhovetsky

Werdiger

et al. 2012

125

144

Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability. aggregation quality control | ALS | insoluble protein deposit | protein folding

“…Examples include carbonylated protein sorting in yeast, mediated by actin filaments in a sir2p-dependent manner (27), the Shigella outer membrane protein IcsA (28), and other bacterial surface structure localization (29) as well as the microtubule-dependent aggrosome localization in mammalian cells (15). Intriguing is the similarity between aggrosome localization to the eukaryotic centrosome (18) and the inclusion bodies to the bacterial division plane. In the former model, putative stem cells exhibited a lower aggregation level as compared with differentiated cells.…”

Section: Discussionmentioning

confidence: 99%

“…In yeast, in vitro immunostaining of carbonylated proteins (16), correlated with aggregated proteins (17), revealed their retention in mother cells (16) although their in vivo dynamics and influence on aging could not be measured. Recently, the polarized asymmetric inheritance of aggrosomes in Drosophila melanogaster neuronal precursor cells as well as in epithelial crypts of patients suffering from the polyglutamine aggregationassociated ataxia type 3 disease was reported (18). Because the low number of inclusion bodies per bacterial cell (13) may lead to their asymmetric partitioning and because of their potential cellular toxicity, we investigated the hypothesis that asymmetric segregation of damaged proteins and their pole-biased accumulation may explain, at least in part, the observed pattern of E. coli aging.…”

mentioning

confidence: 99%

Asymmetric segregation of protein aggregates is associated with cellular aging and rejuvenation

Lindner

Madden

Démarez

et al. 2008

483

622

Aging, defined as a decrease in reproduction rate with age, is a fundamental characteristic of all living organisms down to bacteria. Yet we know little about the causal molecular mechanisms of aging within the in vivo context of a wild-type organism. One of the prominent markers of aging is protein aggregation, associated with cellular degeneracy in many age-related diseases, although its in vivo dynamics and effect are poorly understood. We followed the appearance and inheritance of spontaneous protein aggregation within lineages of Escherichia coli grown under nonstressed conditions using time-lapse microscopy and a fluorescently tagged chaperone (IbpA) involved in aggregate processing. The fluorescent marker is shown to faithfully identify in vivo the localization of aggregated proteins, revealing their accumulation upon cell division in cells with older poles. This accretion is associated with >30% of the loss of reproductive ability (aging) in these cells relative to the new-pole progeny, devoid of parental inclusion bodies, that exhibit rejuvenation. This suggests an asymmetric strategy whereby dividing cells segregate damage at the expense of aging individuals, resulting in the perpetuation of the population.ibpA ͉ inclusion bodies ͉ protein aggregation ͉ small heat-shock protein