Functional characterization of DJ-1: an oxidative response protein Public Deposited

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  • March 21, 2019
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  • Clements, Casey M.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The cancer and Parkinson's disease associated protein DJ-1 functions to protect cells from toxins. Presented here is a mechanistic analysis of DJ-1 cytoprotection. We show that DJ-1 is required for cellular responses to oxidant exposures leading to the protection and survival of cells in adverse conditions. We find that DJ-1 is required for the activity of Nrf2, the master regulator of antioxidant transcription. Furthermore, we show that DJ-1 provides this function by causing Nrf2 to dissociate from its cytsolic inhibitor protein, Keap1. This stabilizes Nrf2, preventing its ubiquitination and degradation in the absence of oxidative stress. DJ-1, therefore, maintains an active-ready pool of Nrf2 protein in cells to respond to oxidative stress. We then present a survey of DJ-1 interacting proteins. We show that DJ-1 remains unbound when the protein is not oxidized, but that during periods of oxidative stress, cysteine-106 in DJ-1 oxidizes causing DJ-1 to bind other proteins. We characterize the interaction of DJ-1 with Cezanne, a deubiquitinating enzyme and negative regulator of NF-[kappa]B. We show that DJ-1 is able to inhibit deubiquitinating enzymes in vitro, including Cezanne and that DJ-1 negates Cezanne mediated inhibition of NF-[kappa]B. Finally, we implicate a broader role of deubiquitinating enzymes in antioxidant responses showing that the ubiquitin editing protein, A20, inhibits the antioxidant transcription factor Nrf2. The results presented herein provide evidence for a mechanism of DJ-1 function as a positive regulator of gene transcription during periods of oxidative stress. DJ-1 functions in this role to protect cells from cytotoxic exposures leading to increased cell survival. Loss of DJ-1 is realized in the death of oxidative sensitive cells, such as neurons in the case of Parkinson's disease. On the other hand, excess DJ-1 activity leads to inappropriate cytoprotection, survival, and cancer. The results summarized in this thesis identify the DJ-1/Nrf2 axis as a target of therapy for the treatment of both cancer and Parkinson's disease.
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  • Ting, Jenny P.-Y.
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