Journal Article

Cellular proteostasis decline in human senescence

Sabath, Niv, Shalgi, Reut, Meller, Anatoly, Soueid-Baumgarten, Sharon, Hadar, Shani, Rozales, Kinneret, Levy-Adam, Flonia, Younis, Amal

2020

Overview

Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

• Publisher: National Academy of Sciences
• Subject: Activating Transcription Factor 6 - metabolism / Aging / Aging - physiology / Alternative splicing / Biological Sciences / Cell Biology / Cell Line / Cell Nucleus - metabolism / Cellular Senescence - physiology / Decoupling / Deterioration / Endoplasmic reticulum / Endoplasmic Reticulum Stress - genetics / Gene expression / Heat shock / Heat stress / Heat tolerance / Heat-Shock Response - genetics / Homeostasis / HSF1 protein / Humans / Localization / Nematodes / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Protein Biosynthesis / Protein folding / Proteins / Proteostasis - genetics / RNA-Seq / Senescence / Splicing / Transcription activation / Transcriptional Activation - physiology / Translation / Unfolded Protein Response - genetics