Won Hoon Choi1,2, Stefanie A.H. de Poot3, Jung Hoon Lee2, Ji Hyeon Kim1, Dong Hoon Han2, Yun Kyung Kim4, Daniel Finley3 & Min Jae Lee1,2,5
Nature Communications 7, Article number: 10963
When in the closed form, the substrate translocation channel of the proteasome core particle (CP) is blocked by the convergent N termini of a-subunits. To probe the role of channel gating in mammalian proteasomes, we deleted the N-terminal tail of a3; the resulting a3DN proteasomes are intact but hyperactive in the hydrolysis of fluorogenic peptide substrates and the degradation of polyubiquitinated proteins. Cells expressing the hyperactive proteasomes show markedly elevated degradation of many established proteasome substrates and resistance to oxidative stress. Multiplexed quantitative proteomics revealed B200 proteins with reduced levels in the mutant cells. Potentially toxic proteins such as tau exhibit reduced accumulation and aggregate formation. These data demonstrate that the CP gate is a key negative regulator of proteasome function in mammals, and that opening the CP gate may be an effective strategy to increase proteasome activity and reduce levels of toxic proteins in cells
1. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea. 2. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea. 3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. 4. Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Seoul 02790, Korea. 5. Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.