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A molecular switch for Cdc48 activity and localization during oxidative stress and aging

Meytal Radzinski, Ohad Yogev, Yarden Yesharim, Esther S. Brielle, Ran Israeli, Rosi Fassler, Naomi Melamed-Book, Nadav Shai, Isaiah T. Arkin, Elah Pick, Tommer Ravid, Maya Schuldiner, Dana Reichmann
doi: https://doi.org/10.1101/733709
Meytal Radzinski
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Ohad Yogev
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Yarden Yesharim
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Esther S. Brielle
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Ran Israeli
2Department of Human Biology, University of Haifa, Haifa 31905, Israel
3Department of Biology and Environment, University of Haifa at Oranim, Tivon 36006, Israel
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Rosi Fassler
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Naomi Melamed-Book
4Bio-Imaging Unit, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Nadav Shai
5Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 7610001, Israel
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Isaiah T. Arkin
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Elah Pick
2Department of Human Biology, University of Haifa, Haifa 31905, Israel
3Department of Biology and Environment, University of Haifa at Oranim, Tivon 36006, Israel
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Tommer Ravid
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Maya Schuldiner
5Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 7610001, Israel
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Dana Reichmann
1Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Safra Campus Givat Ram, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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  • For correspondence: danare@mail.huji.ac.il
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Summary

Control over a healthy proteome begins with the birth of the polypeptide chain and ends with coordinated protein degradation. One of the major players in eukaryotic protein degradation is the essential and highly conserved ATPase, Cdc48 (p97/VCP in mammals). Cdc48 mediates clearance of misfolded proteins from the nucleus, cytosol, ER, mitochondria, and more. Here we dissect the crosstalk between cellular oxidation and Cdc48 activity by identification of a redox-sensitive site, Cys115. By integrating proteomics, biochemistry, microscopy, and bioinformatics, we show that removal of Cys115’s redox-sensitive thiol group leads to accumulation of Cdc48 in the nucleus and consequently, results in severe defects in the oxidative stress response, mitochondrial fragmentation, and a decrease in ERAD and sterol biogenesis. We have thus identified a unique redox switch in Cdc48, which may provide a clearer picture of the importance of Cdc48’s localization in maintaining a “healthy” proteome during oxidative stress and chronological aging in yeast.

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Posted August 13, 2019.
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A molecular switch for Cdc48 activity and localization during oxidative stress and aging
Meytal Radzinski, Ohad Yogev, Yarden Yesharim, Esther S. Brielle, Ran Israeli, Rosi Fassler, Naomi Melamed-Book, Nadav Shai, Isaiah T. Arkin, Elah Pick, Tommer Ravid, Maya Schuldiner, Dana Reichmann
bioRxiv 733709; doi: https://doi.org/10.1101/733709
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A molecular switch for Cdc48 activity and localization during oxidative stress and aging
Meytal Radzinski, Ohad Yogev, Yarden Yesharim, Esther S. Brielle, Ran Israeli, Rosi Fassler, Naomi Melamed-Book, Nadav Shai, Isaiah T. Arkin, Elah Pick, Tommer Ravid, Maya Schuldiner, Dana Reichmann
bioRxiv 733709; doi: https://doi.org/10.1101/733709

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