Biology subjects

Aldea, M.

Publications and source records attributed to Aldea, M..

2 recordsLinked to original sources

bioRxiv2019

Proteostasis collapse halts G1 progression and delimits replicative lifespan

Loss of proteostasis and cellular senescence are key hallmarks of cell aging, but whether they are subject to direct cause-effect relationships is not known. We show that most yeast cells arrest in G1 before death with low nuclear levels of cyclin Cln3, a key activator of Start 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. A mathematical model integrating autocatalytic protein aggregation and a minimal Start network recapitulates empirical observations. As key predictions, G1-cyclin overexpression increases lifespan in a chaperone-dependent manner, and lifespan reduction by enforced protein aggregation is greatly alleviated by increased expression of specific chaperones or cyclin Cln3. Overall, our data indicate the crucial role of chaperone malfunction in setting lifespan in yeast cells, and configure a molecular pathway whereby proteostasis breakdown acts as a direct effector of cell senescence.

cell biology↗

bioRxiv2018

The chaperone-client network subordinates cell-cycle entry to growth and stress

The precise coordination of growth and proliferation has a universal prevalence in cell homeostasis. As a prominent property, cell size is modulated by the coordination between these processes in bacterial, yeast and mammalian cells, but the underlying molecular mechanisms are largely unknown. Here we show that multifunctional chaperone systems play a concerted and limiting role in cell-cycle entry, specifically driving nuclear accumulation of the G1 Cdk-cyclin complex. Based on these findings, we establish and test a molecular competition model that recapitulates cell-cycle-entry dependence on growth rate. As key predictions at a single-cell level, we show that availability of the Ydj1 chaperone and nuclear accumulation of the G1 cyclin Cln3 are inversely dependent on growth rate and readily respond to changes in protein synthesis and stress conditions that alter protein folding requirements. Thus, chaperone workload would subordinate Start to the biosynthetic machinery and dynamically adjust proliferation to the growth potential of the cell.

molecular biology↗