Abstract 20290: Protein Half-Life of Degradation Machineries in Healthy and Stressed Myocardium
Introduction: Proteasomes are essential to maintaining myocardial proteome homeostasis; mounting evidence documents their dysfunction as a cardiac disease driver. Regulation of proteasomal function is complex, involving multidimensional processes including individual subunit function, their assembly into complexes, as well as their heterogeneity, associating partners, and PTMs. Despite our understanding of proteasome subunits in regulation of their targeted substrate degradation, little is known regarding their dynamic turnover.
Methods: We studied 6 mouse genetic strains and their cardiac protein turnover at proteome scale using previously published methods.
Results: The temporal expressions and half-lives of 40+ proteasomal subunits and associating partners were quantified. Proteasomal turnover interquartile ranges were 3.8-7.5 days (20S) and 3.0-5.3 days (19S); the total proteome was 2.6-10.2 days. Collectively examining other public datasets, we revealed distinct patterns of proteasome dynamics in different tissues and model systems. The heart proteasomal turnover is comparable to that of skeletal muscle and brain, but much higher than that of liver. Intriguingly, the turnover rates of 8 other key proteolytic machineries (e.g., LonP) spanned a broader range; the proteasomal subunits had faster turnover, suggesting distinct self-regulatory mechanisms. Among 6 strains, ISO enhanced proteasomal expression, which peaked at 3 days and returned to basal levels. The dynamics of subunit expression were stratified into four groups based on temporal trends/threshold. The 20S expression exhibited 4 patterns: stable (3 subunits), random fluctuations (9), sustained increase (1), and temporary increase (4). DBA/2J and CE/J displayed narrow ranges of proteasomal turnover, implying more synchronized complex assembly. A/J and DBA/2J show a concerted turnover response to ISO; the response of other strains was heterogeneous.
Conclusions: This study elucidates a new mechanism regulating proteasomal function. Along with PTMs and functional studies, this dataset supports future translational investigations as an integrated network to understand the underlying regulatory processes of protein homeostasis in cardiac remodeling.
Author Disclosures: Q. Cao: None. J.S. Polson: None. J. Wang: None. J. Lee: None. S.B. Scruggs: None. M.P. Lam: None. D.C. Ng: None. P. Ping: None. D. Wang: None.
- © 2016 by American Heart Association, Inc.