ECPAS/Ecm29-Mediated 26S Proteasome Disassembly Is an Adaptive Response to Glucose Starvation
Abstract
The 26S proteasome consists of loosely associated 20S catalytic and 19S regulatory complexes. Although approximately half of the proteasomes in eukaryotic cells exist as free 20S complexes, our mechanistic and physiological understanding of 26S dissociation remains incomplete. Here, we show that glucose starvation in mammalian cells results in the uncoupling of 26S holoenzymes into intact 20S and 19S complexes. Subcomplex affinity-purification and quantitative mass spectrometry revealed that Ecm29 proteasome adaptor and scaffold (ECPAS) is a crucial mediator of this structural remodeling. The loss of ECPAS abrogated 26S dissociation, leading to decreased degradation of 20S proteasome substrates, such as puromycylated polypeptides and lysine-less cyclin B. In silico modeling analysis suggested that the conformational changes of ECPAS may commence the disassembly process. ECPAS was also essential for proper endoplasmic reticulum stress response and cell survival during glucose starvation. In addition, we evaluated the role of ECPAS in vivo using the mouse xenograft model and observed that glucose-deprived tumor tissues had significantly elevated 20S proteasome levels. Collectively, our results indicate that the 20S-19S disassembly mediated by ECPAS is a novel mechanism adapting global proteolysis to physiological needs and an effective cellular strategy against proteotoxic stress.
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