DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death

Abstract

DJ-1 is a multifunctional protein that performs functions in transcriptional regulation and oxidative stress, and the loss of its function is believed to result in the onset of Parkinson's disease (PD). In this study, we report that DJ-1 protects against UVinduced cell death through the suppression of the JNK1 signaling pathway. The results of both binding and kinase studies have revealed that MEKK1 is the direct target of DJ-1. The C-terminus of DJ-1 was crucial to the inhibition of the MEKK1 kinase activity. Wild-type DJ-1 sequesters MEKK1 within the cytoplasm and the L166P mutant facilitates the translocation of MEKK1 toward the nucleus without physical association. Both DJ-1 knockdown and pathogenic L166P mutant were determined to be highly susceptible to the UV-induced activation of the MEKK1-SEK1-JNK1 signaling cascade and cell death. Taken together, our findings show that missense mutation in DJ-1 sensitizes cells to stress-induced cell death through the MEKK1-SEK1-JNK1 signaling pathway, a process, which may trigger the early onset of PD.

The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production

“…6,7 Several mechanisms have been reported that explain the anti-apoptotic function of DJ-1, including activation of the PI3K/AKT pathway consecutive to PTEN inhibition, 4 blockage of p53-mediated cell death, 17 activation of the MAP kinase cascade 22 antioxidant genes through Nrf2 stabilization. 23 Interestingly, DJ-1 also protects cells against hypoxia-induced cell death and is required for their adaptation to severe hypoxic stress.…”

DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD

“…DJ-1 also modifies the transcription of antioxidant enzymes by stabilizing the primary regulator of antioxidant responses, nuclear factor erythroid 2-related factor (Clements et al, 2006). DJ-1 suppresses the c-Jun N-terminal kinase (JNK) signaling pathway through its interaction with mitogen-activated protein kinase kinase kinase 1 to repress cell death (Mo et al, 2008). In addition, it interacts with Daxx and sequesters it within the nucleus, preventing its translocation to the cytoplasm and the initiation of apoptotic signaling (Junn et al, 2005).…”

JIP1 binding to RBP-Jk mediates cross-talk between the Notch1 and JIP1-JNK signaling pathway

“…The stained cells were evaluated for localization through confocal microscopy (Leica TCS SPE). 19 In vitro binding assay. The recombinant GST-Notch1-IC and GST-RBP-Jk proteins were expressed in Escherichia coli strain BL21, using the pGEX system as indicated.…”

“…Earlier we have shown that JIP1 may interact with Notch1-IC, 17 and Notch1-IC was mainly present in the nucleus and moderately present in the cytoplasm. [17][18][19] To delineate more precisely the manner in which JIP1 prevents Notch1-IC and RBP-Jk-mediated transcription, we conducted a series of in vitro binding and coimmunoprecipitation experiments. In the in vitro binding studies, an interaction between GST-RBP-Jk and JIP1 was detected on the bead complexes (Figure 4a).…”