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

Reichmann, D.; Radzinski, M.; Yogev, O.; Yesharim, Y.; Brielle, E. S.; Israeli, R.; Fassler, R.; Melamed-Book, N.; Shai, N.; Arkin, I. T.; Pick, E.; Ravid, T.; Schuldiner, M.

doi:10.1101/733709

bioRxiv · 10.1101/733709

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

Reichmann, D.·Radzinski, M.·Yogev, O.·Yesharim, Y.·Brielle, E. S.·Israeli, R.·Fassler, R.·Melamed-Book, N.·Shai, N.·Arkin, I. T.·Pick, E.·Ravid, T.·Schuldiner, M.

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Abstract

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 Cys115s 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 Cdc48s localization in maintaining a \"healthy\" proteome during oxidative stress and chronological aging in yeast.

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Reichmann, D., Radzinski, M., Yogev, O., Yesharim, Y., Brielle, E. S., Israeli, R., Fassler, R., Melamed-Book, N., Shai, N., Arkin, I. T., Pick, E., Ravid, T., Schuldiner, M.. 2019-08-13. A molecular switch for Cdc48 activity and localization during oxidative stress and aging. https://doi.org/10.1101/733709

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