ECPAS/Ecm29-Mediated 26S Proteasome Disassembly Is an Adaptive Response to Glucose Starvation

Choi, W. H.; Yun, Y.; Byun, I.; Lee, S.; Sim, J.; Levi, S.; Kim, S.; Park, S. H.; Jun, J.; Kim, K. P.; Kwon, Y. T.; Han, D.; Chiba, T.; Seok, C.; Glickman, M. H.; Lee, M. J.

doi:10.1101/2022.06.06.495046

bioRxiv · 10.1101/2022.06.06.495046

ECPAS/Ecm29-Mediated 26S Proteasome Disassembly Is an Adaptive Response to Glucose Starvation

Choi, W. H.·Yun, Y.·Byun, I.·Lee, S.·Sim, J.·Levi, S.·Kim, S.·Park, S. H.·Jun, J.·Kim, K. P.·Kwon, Y. T.·Han, D.·Chiba, T.·Seok, C.·Glickman, M. H.·Lee, M. J.

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Abstract

The 26S proteasome consists of loosely associated 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in eukaryotic cells exist as free 20S complexes; however, our mechanistic and physiological understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation in mammalian cells results in the uncoupling of 26S holoenzymes into intact 20S and 19S subcomplexes. 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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Choi, W. H., Yun, Y., Byun, I., Lee, S., Sim, J., Levi, S., Kim, S., Park, S. H., Jun, J., Kim, K. P., Kwon, Y. T., Han, D., Chiba, T., Seok, C., Glickman, M. H., Lee, M. J.. 2022-06-07. ECPAS/Ecm29-Mediated 26S Proteasome Disassembly Is an Adaptive Response to Glucose Starvation. https://doi.org/10.1101/2022.06.06.495046

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