Investigating dysregulation in protein quality control mechanisms in senescent cells
type: CreativeWork
description: Loss of proteostasis and cellular senescence are both considered major hallmarks of ageing, and contribute to the development and maintenance of diseases of ageing. Cellular senescence enacts a programme of stable cell-cycle arrest, accompanied by profound alterations in cellular function including aberrant metabolism and the accumulation of a pro-inflammatory secretory phenotype implicated in driving diseases of ageing. Proteostasis involves pathways and mechanisms which protect cellular protein homeostasis, including synthesis, folding, trafficking and degradation of proteins. Proteostasis loss is implicated in both normal ageing and diseases of ageing in humans, although which mechanisms are disrupted and how is currently unclear. Even less clear is an understanding of the interplay between cellular senescence and proteostasis perturbations. Here, we seek to quantify how proteostasis loss might be mediated by changes to the cell state such as senescence onset, through proteomic and immunofluorescent techniques. We have characterised the proteome, poly-ubiquitylome, and insoluble proteome across different cell-states (proliferating, quiescent, and senescent) between two cell lines, primary human fetal fibroblast IMR-90s, and transformed carcinoma epithelial A549s, following proteotoxic stress. Our findings reveal a generally highly-conserved stress response to proteotoxic insult between all three distinct cell-states, suggesting that senescent cells do not mount a particularly dysregulated response to external stress. Senescent cells did appear to feature slightly dampened accumulation of proteins in the insoluble fraction following stress, a finding which was complemented by our results demonstrating that senescent cells displayed extremely delayed aggresome formation kinetics in contrast with proliferative cells. Aggresome formation dynamics were also altered by perturbations to the autophagy network. We further developed a live-cell fluorescent reporter of prot…
abstract: Loss of proteostasis and cellular senescence are both considered major hallmarks of ageing, and contribute to the development and maintenance of diseases of ageing. Cellular senescence enacts a programme of stable cell-cycle arrest, accompanied by profound alterations in cellular function including aberrant metabolism and the accumulation of a pro-inflammatory secretory phenotype implicated in driving diseases of ageing. Proteostasis involves pathways and mechanisms which protect cellular protein homeostasis, including synthesis, folding, trafficking and degradation of proteins. Proteostasis loss is implicated in both normal ageing and diseases of ageing in humans, although which mechanisms are disrupted and how is currently unclear. Even less clear is an understanding of the interplay between cellular senescence and proteostasis perturbations. Here, we seek to quantify how proteostasis loss might be mediated by changes to the cell state such as senescence onset, through proteomic and immunofluorescent techniques. We have characterised the proteome, poly-ubiquitylome, and insoluble proteome across different cell-states (proliferating, quiescent, and senescent) between two cell lines, primary human fetal fibroblast IMR-90s, and transformed carcinoma epithelial A549s, following proteotoxic stress. Our findings reveal a generally highly-conserved stress response to proteotoxic insult between all three distinct cell-states, suggesting that senescent cells do not mount a particularly dysregulated response to external stress. Senescent cells did appear to feature slightly dampened accumulation of proteins in the insoluble fraction following stress, a finding which was complemented by our results demonstrating that senescent cells displayed extremely delayed aggresome formation kinetics in contrast with proliferative cells. Aggresome formation dynamics were also altered by perturbations to the autophagy network. We further developed a live-cell fluorescent reporter of prot…
author: Al-Mufti, Yasmeen
language: eng
keywords: proteostasis, senescence
license: https://www.repository.cam.ac.uk/bitstreams/8feb00ff-05da-4a59-a11f-12928b8eaf63/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-04-07
date modified: 2026-07-22T22:24:31Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.122834