Proteomics

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Keap1 governs ageing-induced protein aggregation in endothelial cells


ABSTRACT: The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular system. However, the molecular basis of proteostasis decline in vascular cells, as well as its relation to ageing, are not understood. Recent studies have indicated the associations of Nrf2 transcription factor, the critical modulator of cellular stress-response, with ageing and premature senescence. In this report, we outline the significance of protein aggregation in physiological and premature ageing of murine and human endothelial cells (ECs). Our study shows that aged donor-derived and prematurely senescent Nrf2-deficient primary human ECs, but not those overexpressing dominant-negative Nrf2, exhibit increased accumulation of protein aggregates. Such phenotype is also found in the aortas of aged mice and young Nrf2 tKO mice. Ageing-related loss of proteostasis in ECs depends on Keap1, well-known repressor of Nrf2, recently perceived as a key independent regulator of EC function. Ageing-induced deposition of protein aggregates in ECs is associated with impaired autophagy and can be counteracted by Keap1 depletion or rapamycin treatment. Our results show that Keap1:Nrf2 protein balance predominates Nrf2 transcription-dependent mechanisms in governing proteostasis and ageing in ECs.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Dominik Cysewski  

LAB HEAD: Anna Grochot-Przęczek

PROVIDER: PXD018969 | Pride | 2020-08-12

REPOSITORIES: pride

Dataset's files

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Action DRS
812042892gro_Mocksoluble1.raw Raw
812042893gro_Mocksoluble2.raw Raw
812042895gro_Mocksoluble4.raw Raw
812042896gro_Mocksoluble5.raw Raw
812042897gro_Nrfsoluble1.raw Raw
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The breach of proteostasis, leading to the accumulation of protein aggregates, is a hallmark of ageing and age-associated disorders, up to now well-established in neurodegeneration. Few studies have addressed the issue of dysfunctional cell response to protein deposition also for the cardiovascular system. However, the molecular basis of proteostasis decline in vascular cells, as well as its relation to ageing, are not understood. Recent studies have indicated the associations of Nrf2 transcript  ...[more]

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