L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL
© Ren et al.; licensee BioMed Central Ltd. 2012
Received: 25 March 2012
Accepted: 6 August 2012
Published: 14 August 2012
Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson’s disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XL and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown.
We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XL more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.
Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-XL functions.
KeywordsParkinson’s disease DJ-1 L166P Mitochondria Apoptosis Bcl-XL Bax UVB
Parkinson’s disease (PD), a common neurodegenerative movement disorder, is associated with progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) . DJ-1, a product of DJ-1/PARK7 gene, was originally identified as an oncogene protein that protects cells against stress through multiple pathways including gene transcription regulation, protein stabilization, signal transduction and reactive oxygen species (ROS) elimination [2, 3]. Recently, DJ-1 has attracted more attention due to its involvement in familial early onset PD as its deletion mutants or point mutations including L166P, A104T, M26I, D149A, E64D and L10P cause PD [1, 4, 5]. DJ-1(L166P) was the most commonly studied and traditionally considered as “loss of function by degradation” because of its instability and misfolded structure compared with wild-type DJ-1 [6–8]. In addition, DJ-1(L166P) exists as a monomer, whereas wild-type DJ-1 exists as homodimers in cells [6, 9]. However, many lines of recent evidence indicated that DJ-1(L166P) renders cells more susceptible to cell death under death stimuli [10–14].
Mitochondrial dysfunction is the key and common causative factor for pathogenesis of PD [1, 15–19]. In PD patients and experimental PD models, dopaminergic neurodegeneration is caused at least partly by activation of mitochondria-dependent programmed cell death 2(PCD) pathways [20, 21]. For instance, positive Bax, caspase-3, caspase-9 have been observed in SNpc dopaminergic neurons in PD models [22–24]. In addition, PD-associated proteins such as PINK1, parkin and DJ-1 directly affect mitochondrial functions [25–29]. DJ-1 deficiency leads to impairments of mitochondrial connectivity, fusion rates, membrane potential (ΔΨm), respiratory capacity and ROS scavenging [25, 30–33]. Interestingly, wild-type DJ-1 partially localized in mitochondria and DJ-1 mutants including L166P are more prone to mitochondrial localization [5, 8, 12, 34, 35]. Moreover, both wild-type DJ-1 and DJ-1(L166P) are enriched in the mitochondrial fraction under death stimuli [34, 36]. So, it is possible that DJ-1(L166P) impairs cells or neurons by “gain of function by translocation to mitochondria”. In addition, the physiological roles of their translocation to mitochondria under oxidative stress are still unclear because wild-type DJ-1 translocation to mitochondria under oxidative stress is required for its oxidation of Cys106 , but DJ-1(L166P) can not be oxidized , suggesting that these two proteins may differentially function in mitochondria.
Recently, we reported that wild-type DJ-1 translocates to mitochondria and binds to Bcl-XL in response to UVB irradiation and inhibits Bcl-XL rapid degradation and mitochondrial apoptosis pathway induced by UVB irradiation . However, the roles of DJ-1(L166P) in mitochondria during oxidative stress are largely unknown. In this study, we further showed that DJ-1(L166P) binds more tightly to Bcl-XL than wild-type DJ-1. Under UVB irradiation, DJ-1(L166P) translocates to mitochondria to dissociate Bax from Bcl-XL by its interaction with Bcl-XL, resulting in an increased susceptibility of cells to UVB irradiation-induce cell death. Our results suggest that DJ-1 and DJ-1(L166P) differentially regulate Bcl-XL functions in control of the mitochondrial apoptotic pathway.
Subcellular distribution of wild-type DJ-1 and DJ-1(L166P)
Interactions between Bcl-XLand DJ-1(L166P)
Requirement of the C-terminal of Bcl-XLfor DJ-1(L166P) binding
Dissociation of Bax from Bcl-XLby DJ-1(L166P)
DJ-1(L166P) promotes cell death by interfering with Bcl-XL/Bax heterodimerization
The mitochondrial localization of Bax is important for its ability to induce cell death . Because DJ-1 and DJ-1(L166P) re-distribute to mitochondria upon UVB irradiation but differentially influence Bcl-XL, we performed cytosolic and mitochondrial fractionation assays and MTT assays to examine the effects of DJ-1 and DJ-1(L166P) on mitochondrial Bax translocation and cell viability. We performed experiments in H1299 cells, a p53 null cell line to exclude the possibility that DJ-1 inhibits Bax transcription by binding to p53 [45–47]. Because endogenous DJ-1 expression is abundant , we constructed a H1299 cell line stably transfected with sh-DJ-1 to silence endogenous DJ-1 to examine the effects of exogenous wild-type DJ-1 and DJ-1(L166P).
Many studies have shown that wild-type DJ-1 and DJ-1(L166P) are partially localized in mitochondria [5, 8, 12, 34, 35], and that their mitochondrial distribution is enhanced under death stimuli [34, 36]. Several lines of evidence indicate that wild-type DJ-1 exhibits its cytoprotective roles by maintaining mitochondrial integrity, fusion rates, membrane potential, respiratory capacity and ROS elimination [25, 30–33].
In our previous study, we identified that wild-type DJ-1 is a novel partner of Bcl-XL in mitochondria, to stabilize Bcl-XL. Here, we found that DJ-1(L166P) binds to Bcl-XL as well. However, DJ-1(L166P) does not stabilize Bcl-XL but dissociates Bax from Bcl-XL. The binding ability of DJ-1(L166P) to Bcl-XL is stronger than that of wild-type DJ-1 (Figure 2B). In contrast to DJ-1 that interacts with Bcl-XL dependent on its oxidation , DJ-1(L166P) interacts with Bcl-XL independent on its oxidation as DJ-1(L166P) is a loss of oxidized form . In addition, DJ-1(L166P) binds to the C-terminus of Bcl-XL (Figure 3A and 3B) which is required for Bcl-XL/Bax heterodimer formation , but wild-type DJ-1 mainly binds to middle regions (Figure 3A) containing BH1, BH2 and BH3 domains which are essential for Bcl-XL stability [49, 50]. Wild-type DJ-1 and DJ-1(L166P) that bind to different domains of Bcl-XL may be due to the fact that L166P mutant interrupts the normal folding and exposes new domains or amino acid sites [38, 51, 52]. Taken together, our study suggests that the different roles of DJ-1 and DJ-1(L166P) in mitochondria may result from the different oxidative status of these two proteins and from their functioning differentially in mitochondria.
L166P mutant prevents normal folding of wild-type DJ-1 and itself is instable with a rapid degradation via UPS [6, 7, 51, 52]. However, DJ-1(L166P) appears not only to be “loss of function” of wild-type DJ-1. It also forms larger complexes with other proteins but not wild-type DJ-1 . Although DJ-1(L166P) loses the ability to bind to proteins that wild-type DJ-1 does, such as Daxx , DJ-1(L166P) existing as a monomer in cells may allow it to gain an ability to bind to proteins that wild-type DJ-1 does not. For instance, DJ-1(L166P) and DJ-1(M26I) bind more TTRAP than wild-type DJ-1 does, and they block the protective activity of TTRAP, leading to cell death . Wild-type DJ-1 represses UV-induced JNK activation to protects cells, but DJ-1(L166P) significantly activates JNK pathway to promote cell death in response to UV irradiation . As much more DJ-1(L166P) is translocated to mitochondria than wild-type DJ-1 under UVB stimulation, and DJ-1(L166P), but not wild-type DJ-1, dissociates Bax from mitochondrial Bcl-XL, it is therefore possible that DJ-1(L166P) may gain functions by translocation to mitochondria to affect mitochondrial pathway. We also found that another PD-associated mutant DJ-1(M26I) mainly distributes in mitochondria and binds to Bcl-XL, similar to DJ-1(166P) (Additional file 1: Figure S2). These results suggest that the mitochondrial Bcl-XL/Bax pathway influenced by mutant DJ-1 might be a common mechanism involved in mutant DJ-1-associated PD pathogenesis.
Mitochondrial dysfunction is a key feature involved in both sporadic and genetic forms of PD [1, 15–19]. Although familial PD is rare, to understand the mechanisms and functions of familial PD-associated proteins in mitochondria may shed light on the pathogenesis of PD. Our findings suggest that wild-type DJ-1 and DJ-1(L166P) differentially mediate Bcl-XL functions providing us to further understand the pathogenesis of PD.
We found that a small portion of wild-type DJ-1 and most of DJ-1(L166P) is presented in mitochondria and wild-type DJ-1 and DJ-1(L166P) increased in mitochondria in response to UVB irradiation. DJ-1(L166P) binds to mitochondrial Bcl-XL more tightly than wild-type DJ-1 and UVB irradiation further promotes their binding affinity. Unlike wild-type DJ-1, DJ-1(L166P) fails to stabilize Bcl-XL, but it dissociates Bax from Bcl-XL that leading Bax enrichment in outer mitochondrial membrane and subsequently triggers cell death in response to UV irradiation. Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating Bcl-XL functions. Our study provides a novel insight into the underlying mechanisms of PD pathogenesis.
Materials and methods
Cell culture and plasmid transfection
Human HEK293 cells, a human kidney cell line, and H1299 cells, a human lung cancer cell line, were maintained in DMEM (Dulbecco’s modified Eagle’s medium) supplemented with 10% fetal bovine serum (Hyclone, USA). Plasmid transfections were performed using Lipofectamine2000 reagent (Invitrogen, USA).
UVB irradiation treatment
HEK293 or H1299 cells were irradiated with UVB using a UV crosslinker. Briefly, the cultured cells covered with a thin layer of phosphate buffer solution (PBS, pH 7.4), were exposed to UVB irradiation (312 nm) with 80 mJ/cm2 with a UV crosslinker (SCIENTZ03-II, Ningbo, China). After UVB irradiation, the cells were cultured for 16 hours and subsequently subjected to additional experiments.
siRNA or shRNA knockdown
si-DJ-1328 was described previously . siRNA against human Bcl-XL mRNA was purchased from GenePharma (GenePharma, Shanghai, China) with the following sequences: sense: 5′-GAGAUGCAGGUAUUGGUGATT-3′, anti-sense: 5′-UCACCAAUACCUGCAUCUCTT-3′. The oligonucleotides were transfected with Oligofectamine reagent (Invitrogen, USA). Briefly, cultured cells were washed with Opti-MEM medium (Invitrogen) and then transfected with siRNA using Oligofectamine reagent in Opti-MEM medium without serum. Six hours after transfection, the culture medium was replaced with fresh complete medium. The cells were subjected to further experiments 72 hours after transfection. pGPU6/GFP/Neo-sh-DJ-1 encoding a short hairpin RNA (shRNA) against nucleotide 328 to 346 of human DJ-1 mRNA (sh-DJ-1) or a negative control short hairpin (sh-NC) was constructed by GenePharma (GenePharma, Shanghai, China). H1299 cells stably expressing sh-NC or sh-DJ-1 were obtained by selection with 200 μg/ml Geneticin (Invitrogen, USA) after transfection.
Full-length DJ-1 in p3 × Flag-myc-cmv-24, pET-15b, pDsRed-N1, pmyc-cmv-24 and pGEX-5x-1, and pET-21a-Bcl2, pET-21a-Bax, pET-21a-Bcl-XL, pEGFP-C2-Bcl-XL, p3 × Flag-myc-cmv-24-Bcl-XL, pGEX-5x-1-Bcl-XL(1–85), pGEX-5x-1-Bcl-XL(86–195) and pGEX-5x-1-Bcl-XL(196–233) were described previously . pEGFP-C2-Bcl-XL(1–195) and pEGFP-C2-Bcl-XL(196–233) were created by subcloning PCR products into pEGFP-C2 at its EcoRI/SalI sites. The PCR products were amplified with the following primers: 5′-CGGAATTCATGTCTCAGAGCAAC-3′ and 5′-GCGTCGACTCAATAGAGTTCCACAAA-3′ for 1-195aa; 5′-CGGAATTCGGGAACAATGCAGCA-3′ and 5′-GCGTCGACTCATTTCCGACTGAAG-3′ for 196-233aa. DJ-1(L166P) and DJ-1(M26I) mutants were obtained by site-directed mutagenesis using wild-type DJ-1 plasmids as template with the following primers: 5′-CCTGCAATTGTTGAAGCCCTGGAATG-3′ and 5′-CGCAAACTCGAAGCTGGTCCCAG-3′, for DJ-1(L166P); 5′-GTAGATGTCATTAGGCGA-3′ and 5′-GGTGACCTTAATCCCAGC-3′, for DJ-1(M26I); respectively. Two synonymous mutants, p3 × Flag-myc-cmv-24-DJ-1(s) and p3 × Flag-myc-cmv-24-DJ-1(L166P)(s), that are resistant to si-DJ-1328 and sh-DJ-1 were described previously .
HEK293 cells were washed with PBS and fixed with 4% paraformaldehyde. After being blocked with 4% fetal bovine serum containing 0.25% Triton X-100 in PBS, the cells incubated with rabbit anti-myc polyclonal antibodies (Santa Cruz Biotechnology, USA) followed by an incubation with rhodamine-conjugated donkey anti-rabbit IgG (Santa Cruz biotech, Inc). After staining with DAPI (4′,6-diamidino-2-phenylindole), the labeled cells were observed using an inverted fluorescent microscope (Olympus, IX71).
GST pulldown assay
Equal amounts of GST or GST-fused proteins (20 μg) expressed by Escherichia coli strain JM109 were incubated with 20 μl of glutathione agarose beads (Pharmacia, USA) for 30 min at 4°C. After washing three times with ice-cold PBS, the beads were incubated with 50 μg of His-fused protein expressed by Escherichia coli strain BL21 for 2 hours at 4°C. After incubation, the beads were washed five times with ice-cold HNTG buffer (20 mM Hepes-KOH, pH 7.5, 100 mM NaCl, 0.1% Triton X-100 and 10% glycerol). Bound proteins were eluted from the beads and subjected to immunoblot analysis with specific antibodies. The input represents 10% of the protein that was incubated with GST or a GST-fused protein. The inputs of purified GST and GST fusion proteins are stained with Coomassie Brilliant Blue (CBB) or anti-GST antibody.
The cells were lysed in 1 ml cell lysis buffer (50 mM Tris–HCl pH 7.5 buffer containing 150 mM NaCl, 1% NP40 and 0.5% deoxycholate) supplemented with the protease inhibitor cocktail (Roche, USA) for 30 min at 4°C. After centrifugation at 12,000 g for 15 min at 4°C, the supernatants were incubated with appropriate antibodies coupled to protein G Sepharose (Roche, USA). The immunoprecipitants were then washed five times with cell lysis buffer. Bound proteins and cell lysates were subjected to immunoblot analysis. The input represents 10% of the supernatant used in the co-immunoprecipitation experiment.
Immunoblot analysis and antibodies
Proteins were separated by 12% or 15% SDS-PAGE and subjected to immunoblot analysis with specific antibodies. The following primary antibodies were used: Monoclonal anti-Bcl2, anti-Bcl-XL, anti-GFP, anti-GST, anti-Tom20, anti-Ub and polyclonal anti-Myc, anti-Bax, anti-Max antibodies were purchased from Santa Cruz Biotechnology. Polyclonal anti-Bcl-XL, anti-cleaved caspase-3 and anti-PARP antibodies were from Cell Signaling. Polyclonal anti-DJ-1 antibodies were purchased from Chemicon. Monoclonal anti-Flag-HRP and anti-α-Tubulin antibodies were purchased from Sigma. Monoclonal anti-GAPDH antibody was from Millipore. The secondary antibodies, sheep anti-mouse IgG-HRP and anti-rabbit IgG-HRP were purchased from Amersham Pharmacia Biotech. The proteins were visualized using an ECL detection kit (Amersham Pharmacia Biotech). Immunoblot densitometric analysis of data from three independent experiments was performed using Photoshop 7.0 (Adobe, USA).
Subcellular fractionation assay
The cytosolic and mitochondrial fractions were isolated using Mitochondria Isolation Kit for Cultured Cells (Beyotime, China). The total cell lysates and isolated fractions were subjected to immunoblot analysis with specific antibodies. Tom20, α-Tubulin and Max served as the mitochondrial, cytosolic and nuclear maker, respectively.
Cell viability assay
The cell viability was measured by MTT (methylthiazoletetrazolium) assay. Briefly, the cells were washed with DMEM without phenol red (Gibco, USA) and incubated with 0.5 mg/ml MTT (Sigma) for three hours. The medium was removed and the formazan crystals were dissolved in DMSO (dimethyl sulfoxide). Cell viability was measured by spectrometry at OD570. The data were normalized to a control and the ratios are presented as means ± S.E.M from three independent experiments.
The data were analyzed by one-way analysis of variance (ANOVA) using origin 6.0 software (Originlab, USA). Values are shown as mean ± S.E.M.
Analysis of variance
Coomassie brilliant blue
Enhanced green fluorescent proteins
Phosphate buffer solution
Reactive oxygen species
Substantia nigra pars compacta
Ubiquitin proteasome system
This work was supported in part by the National High-tech Research and Development program of China 973-projects (2011CB504102), the National Natural Sciences Foundation of China (No. 30970921 and 31100768) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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