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

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. The ability of cells to asymmetrically segregate aggregates during division has become an increasingly fascinating topic in the field of aggregation and aging. In this study, Kaganovich and colleagues advance our cellular understanding of aging by showing that confinement of aggregated proteins is precisely regulated by compartmentalization in inclusions and is key to preventing generational transfer of aggregated proteins. The authors provide mechanistic insight that enables control of asymmetric aggregate inheritance.