Confinement to Organelle-Associated Inclusion Structures Mediates Asymmetric Inheritance of Aggregated Protein in Budding Yeast

Abstract

The division of the S. cerevisiae budding yeast, which produces one mother cell and one daughter cell, is asymmetric with respect to aging. Remarkably, the asymmetry of yeast aging coincides with asymmetric inheritance of damaged and aggregated proteins by the mother cell. Here, we show that misfolded proteins are retained in the mother cell by being sequestered in juxtanuclear quality control compartment (JUNQ) and insoluble protein deposit (IPOD) inclusions, which are attached to organelles. Upon exposure to stress, misfolded proteins accumulate in stress foci that must be disaggregated by Hsp104 in order to be degraded or processed to JUNQ and IPOD. Cells that fail to deliver aggregates to an inclusion pass on aggregates to subsequent generations.

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

“…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).…”

“…Upon misfolding, substrates localize to transient stress foci (SFs), which concentrate chaperones, holdases, and disaggregases (7). SFs are dynamic IBs that form in response to acute stress and may participate in the triage decision of whether to refold, degrade, or aggregate misfolded proteins (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.…”

“…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.…”

“…Upon misfolding, substrates localize to transient stress foci (SFs), which concentrate chaperones, holdases, and disaggregases (7). SFs are dynamic IBs that form in response to acute stress and may participate in the triage decision of whether to refold, degrade, or aggregate misfolded proteins (7). As misfolded substrates accumulate, and especially in response to external stresses, they accumulate in two quality-control IBs: Proteins targeted for degradation are directed to the JUNQ compartment and proteins that are targeted for active aggregation are directed to an insoluble IPOD compartment (10).…”