The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag

Indrajit Sahu, Sachitanand M. Mali, Prasad Sulkshane, Cong Xu, Andrey Rozenberg, Roni Morag, Manisha Priyadarsini Sahoo, Sumeet K. Singh, Zhanyu Ding, Yifan Wang, Sharleen Day, Yao Cong, Oded Kleifeld (), Ashraf Brik () and Michael H. Glickman ()
Additional contact information
Indrajit Sahu: Faculty of Biology, Technion–Israel Institute of Technology
Sachitanand M. Mali: Schulich faculty of Chemistry, Technion–Israel Institute of Technology
Prasad Sulkshane: Faculty of Biology, Technion–Israel Institute of Technology
Cong Xu: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Andrey Rozenberg: Faculty of Biology, Technion–Israel Institute of Technology
Roni Morag: Faculty of Biology, Technion–Israel Institute of Technology
Manisha Priyadarsini Sahoo: Faculty of Biology, Technion–Israel Institute of Technology
Sumeet K. Singh: Schulich faculty of Chemistry, Technion–Israel Institute of Technology
Zhanyu Ding: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Yifan Wang: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Sharleen Day: University of Pennsylvania
Yao Cong: State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Oded Kleifeld: Faculty of Biology, Technion–Israel Institute of Technology
Ashraf Brik: Schulich faculty of Chemistry, Technion–Israel Institute of Technology
Michael H. Glickman: Faculty of Biology, Technion–Israel Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract The proteasome, the primary protease for ubiquitin-dependent proteolysis in eukaryotes, is usually found as a mixture of 30S, 26S, and 20S complexes. These complexes have common catalytic sites, which makes it challenging to determine their distinctive roles in intracellular proteolysis. Here, we chemically synthesize a panel of homogenous ubiquitinated proteins, and use them to compare 20S and 26S proteasomes with respect to substrate selection and peptide-product generation. We show that 20S proteasomes can degrade the ubiquitin tag along with the conjugated substrate. Ubiquitin remnants on branched peptide products identified by LC-MS/MS, and flexibility in the 20S gate observed by cryo-EM, reflect the ability of the 20S proteasome to proteolyze an isopeptide-linked ubiquitin-conjugate. Peptidomics identifies proteasome-trapped ubiquitin-derived peptides and peptides of potential 20S substrates in Hi20S cells, hypoxic cells, and human failing-heart. Moreover, elevated levels of 20S proteasomes appear to contribute to cell survival under stress associated with damaged proteins.

Date: 2021
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DOI: 10.1038/s41467-021-26427-0

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