PgmNr Y3050: Membrane trafficking underlies aging and rejuvenation.

Authors:
Kiersten A. Henderson 1 ; Jason V. Rogers 2 ; Patricia Gordon 1 ; Netty Lim 1 ; Daniel E. Gottschling 1,2


Institutes
1) Fred Hutchinson Cancer Research Center, Seattle, WA; 2) Calico Life Sciences, LLC, South San Francisco, CA.


Keyword: Protein Sorting and Turnover

Abstract:

Replicative aging is asymmetric – mother cells age but produce daughter cells with full lifespans. We recently identified that mother-daughter asymmetry of the plasma membrane H+-ATPase, Pma1, underlies age asymmetry (Henderson et al., eLife, 2014). We found that Pma1 accumulates at the plasma membrane of mother cells during aging, but that daughter cells have very low levels of Pma1.

Pma1 is the major regulator of cytosolic pH (Serrano et al., MCB, 1986).  By accumulating at the plasma membrane of mother cells during aging, Pma1 causes an increase in cytosolic pH that limits lifespan by antagonizing vacuolar function. However, nascent daughter cells (buds) and newborn daughters have very low levels of Pma1. Thus, the asymmetric distribution of Pma1 allows daughter cells to achieve normal cytosolic pH and vacuole function, and they are born young.

Because mother-daughter asymmetry of Pma1 underlies aging and rejuvenation, we sought to identify how the spatial distribution of Pma1 is achieved. We performed high-throughput microscopy screens and identified mutants that disrupted Pma1 asymmetry (i.e. increased levels of Pma1 at the bud plasma membrane). We found that disrupting endocytosis, endocytic trafficking, and sorting at the late golgi increases the level of Pma1 in nascent daughter cells.

Because these processes contribute to Pma1 asymmetry, this suggests that they are spatially regulated to occur differently between mother cells and buds and/or cell cycle regulated. We are currently dissecting how these processes are regulated to establish Pma1 asymmetry and we will determine how each process influences asymmetry of cytosolic pH, vacuole function, and lifespan.



Yeast Database Genetic Index
1. gene symbol: Pma1; systematic name: YGL008C