Proteasome lid bridges mitochondrial stress with Cdc53/Cullin1 NEDDylation status
L. Bramasole,
A. Sinha,
S. Gurevich,
M. Radzinski,
Y. Klein,
N. Panat,
E. Gefen,
T. Rinaldi,
D. Jimenez-Morales,
J. Johnson,
N.J. Krogan,
N. Reis,
D. Reichmann,
M.H. Glickman,
E. Pick
Affiliations
L. Bramasole
Department of Human Biology, The Faculty of Natural Sciences, University of Haifa, Haifa 3190500, Israel; Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel
A. Sinha
Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel
S. Gurevich
Department of Biology, Technion–Israel Institute of Technology, 3200000 Haifa, Israel
M. Radzinski
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 9190400, Israel
Y. Klein
Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel
N. Panat
Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel
E. Gefen
Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel
T. Rinaldi
Department of Biology and Biotechnology, University of Rome ‘‘La Sapienza’’, Rome 00185, Italy
D. Jimenez-Morales
Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
J. Johnson
Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
N.J. Krogan
Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
N. Reis
Department of Biology, Technion–Israel Institute of Technology, 3200000 Haifa, Israel
D. Reichmann
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 9190400, Israel
M.H. Glickman
Department of Biology, Technion–Israel Institute of Technology, 3200000 Haifa, Israel
E. Pick
Department of Human Biology, The Faculty of Natural Sciences, University of Haifa, Haifa 3190500, Israel; Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel; Corresponding author at: Department of Biology and Environment, The Faculty of Natural Sciences, University of Haifa at Oranim, Tivon 3600600, Israel.
Cycles of Cdc53/Cullin1 rubylation (a.k.a NEDDylation) protect ubiquitin-E3 SCF (Skp1-Cullin1-F-box protein) complexes from self-destruction and play an important role in mediating the ubiquitination of key protein substrates involved in cell cycle progression, development, and survival. Cul1 rubylation is balanced by the COP9 signalosome (CSN), a multi-subunit derubylase that shows 1:1 paralogy to the 26S proteasome lid. The turnover of SCF substrates and their relevance to various diseases is well studied, yet, the extent by which environmental perturbations influence Cul1 rubylation/derubylation cycles per se is still unclear. In this study, we show that the level of cellular oxidation serves as a molecular switch, determining Cullin1 rubylation/derubylation ratio. We describe a mutant of the proteasome lid subunit, Rpn11 that exhibits accumulated levels of Cullin1-Rub1 conjugates, a characteristic phenotype of csn mutants. By dissecting between distinct phenotypes of rpn11 mutants, proteasome and mitochondria dysfunction, we were able to recognize the high reactive oxygen species (ROS) production during the transition of cells into mitochondrial respiration, as a checkpoint of Cullin1 rubylation in a reversible manner. Thus, the study adds the rubylation cascade to the list of cellular pathways regulated by redox homeostasis. Keywords: 26S proteasome, Mitochondria, NEDD8/Rub1, Rpn11, Thiol switch, Ubiquitin