Proteostasis collapse, a hallmark of aging, hinders the chaperone-Start network and arrests cells in G1.

David F Moreno,Kirsten Jenkins,Attila Csikasz-Nagy,Sandrine Morlot,Gilles Charvin,Martí Aldea

doi:10.7554/elife.48240

Abstract

Loss of proteostasis and cellular senescence are key hallmarks of aging, but direct cause-effect relationships are not well understood. We show that most yeast cells arrest in G1 before death with low nuclear levels of Cln3, a key G1 cyclin extremely sensitive to chaperone status. Chaperone availability is seriously compromised in aged cells, and the G1 arrest coincides with massive aggregation of a metastable chaperone-activity reporter. Moreover, G1-cyclin overexpression increases lifespan in a chaperone-dependent manner. As a key prediction of a model integrating autocatalytic protein aggregation and a minimal Start network, enforced protein aggregation causes a severe reduction in lifespan, an effect that is greatly alleviated by increased expression of specific chaperones or cyclin Cln3. Overall, our data show that proteostasis breakdown, by compromising chaperone activity and G1-cyclin function, causes an irreversible arrest in G1, configuring a molecular pathway postulating proteostasis decay as a key contributing effector of cell senescence.

Highlights

Like most other cell types, individual yeast cells display a finite lifespan as they undergo subsequent replication cycles and, due to their relative simplicity, have become a very fruitful model to study the causal interactions among the different hallmarks of cell aging
Old cells selected with the mother-enrichment program (MEP) displayed a larger fraction in G1 compared to young mother cells (Figure 1—figure supplement 1A,B)
We show that most yeast cells arrest in G1 before death and display low nuclear levels of cyclin Cln3, a key activator of Start that is sensitive to chaperone status (Moreno et al, 2019; Parisi et al, 2018; Verges et al, 2007)

Summary

Introduction

Like most other cell types, individual yeast cells display a finite lifespan as they undergo subsequent replication cycles and, due to their relative simplicity, have become a very fruitful model to study the causal interactions among the different hallmarks of cell aging. Proteostasis deterioration is a universal hallmark of cellular aging (Kaushik and Cuervo, 2015; Klaips et al, 2018; Labbadia and Morimoto, 2015; LopezOtın et al, 2013), and yeast cells have been the paradigm to study the mechanisms of asymmetric segregation of protein aggregates or deposits and their relevance in aging (Hill et al, 2017).

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Conclusion