Abstract
The long-lived proteome constitutes a pool of exceptionally stable proteins with limited turnover. Previous studies on ubiquitin-mediated protein degradation primarily focused on relatively short-lived proteins; how ubiquitylation modifies the long-lived proteome and its regulatory effect on adult lifespan is unclear. Here we profile the age-dependent dynamics of long-lived proteomes in Drosophila by mass spectrometry using stable isotope switching coupled with antibody-enriched ubiquitylome analysis. Our data describe landscapes of long-lived proteins in somatic and reproductive tissues of Drosophila during adult lifespan, and reveal a preferential ubiquitylation of older long-lived proteins. We identify an age-modulated increase of ubiquitylation on long-lived histone 2A protein in Drosophila, which is evolutionarily conserved in mouse, monkey, and human. A reduction of ubiquitylated histone 2A in mutant flies is associated with longevity and healthy lifespan. Together, our data reveal an evolutionarily conserved biomarker of aging that links epigenetic modulation of the long-lived histone protein to lifespan.
Highlights
The long-lived proteome constitutes a pool of exceptionally stable proteins with limited turnover
For young animals at 5d post-eclosion, fly diet was switched from 15N-labeled heavy form to natural 14N-labeled light form, such that newly synthesized proteins during adult lifespan could incorporate 14N, allowing the separation of the newer proteome from older proteome by mass spectrometry
Mass spectrometry analysis of 5d old animals fed with 15N-diet from in utero showed that 15N-labeled peptides accounted for more than
Summary
The long-lived proteome constitutes a pool of exceptionally stable proteins with limited turnover. Previous studies on ubiquitin-mediated protein degradation primarily focused on relatively short-lived proteins; how ubiquitylation modifies the long-lived proteome and its regulatory effect on adult lifespan is unclear. We identify an age-modulated increase of ubiquitylation on long-lived histone 2A protein in Drosophila, which is evolutionarily conserved in mouse, monkey, and human. Our data reveal an evolutionarily conserved biomarker of aging that links epigenetic modulation of the long-lived histone protein to lifespan. For long-lived histone proteins, PTM through methylation and acetylation constitutes age-modulated epigenetic changes that profoundly impacts adult lifespan[28,29,30]. Our analysis reveals an age-modulated ubiquitylation on longlived histone 2A protein (ubH2A) in Drosophila, which is evolutionarily conserved in mouse, monkey, and human. Our data reveal an evolutionarily conserved biomarker of aging that links epigenetic modulation to adult lifespan
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