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Vol. 16, Issue 6, 2926-2933, June 2005
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* Russell Grimwade School of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia;
Victorian Bioinformatics Consortium, Monash University, Clayton, VIC 3800, Australia;
Children's Cancer Centre, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia;
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia; and
|| Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3010, Australia
Submitted December 17, 2004;
Revised March 14, 2005;
Accepted March 24, 2005
Monitoring Editor: Donald Newmeyer
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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A family of intracellular proteases called caspases implement programmed cell death (Ekert et al., 1999
). The activity of caspases is regulated by a family of inhibitor of apoptosis proteins (IAPs) that bind and neutralize active caspases (Deveraux and Reed, 1999). For example, the inhibitor MIHA/XIAP/hILP/BIRC4 can bind and inhibit processed caspases 3, 7, and 9 (Duckett et al., 1996; Liston et al., 1996; Uren et al., 1996; Deveraux et al., 1997, 1998). This damping of caspase activity provides a layer of regulation over the cell death-promoting activities of this family of effector proteases.
In mammalian cells, signals for cell death can lead to rupture of the mitochondrial outer membrane, and under these conditions the inhibition of caspases can be antagonized by the mitochondrial proteins DIABLO/Smac (Du et al., 2000; Verhagen et al., 2000) and HtrA2/Omi (Suzuki et al., 2001; Martins et al., 2002; Verhagen et al., 2002). Structural studies (Chai et al., 2000; Liu et al., 2000; Wu et al., 2000) have shown that purified DIABLO is a homodimer (Chai et al., 2000), and each DIABLO dimer can bind to the BIR domains of inhibitor proteins via contacts made to the N-terminal residues of DIABLO (Liu et al., 2000; Wu et al., 2000). The avid interaction DIABLO makes with the inhibitor MIHA competes the inhibitor away from active caspase 9, freeing caspase 9 to proteolytically activate downstream caspases (Ekert et al., 2001).
Mouse DIABLO is translated as a 237-residue precursor protein (preDIABLO) with an N-terminal presequence that must be cleaved to generate the mature form with the amino-terminal sequence A54VPI (Du et al., 2000; Verhagen et al., 2000). Here, we provide evidence that the N-terminal pre-sequence of DIABLO precursor is a bipartite, stop-transfer type targeting signal. We suggest that the precursor form of DIABLO is recognized and translocated through the mitochondrial outer membrane via the translocase in the outer mitochondrial membrane (TOM) complex and in the intermembrane space is transferred to the translocase in the inner mitochondrial membrane (TIM23) complex. The stop-transfer sequence is cleaved by the IMP complex, an oligomeric inner membrane peptidase. We have identified metazoan homologues of the catalytically active subunits of the IMP complex, hitherto only identified in yeast, and show the mammalian orthologues function to process, and thereby activate, DIABLO/Smac in mitochondria.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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) for analysis by confocal microscopy or into pYADE4 under the control of the ADH2 promoter (Brunelli and Pall, 1993) for the complementation assays. FLAG-tagged MmImp1 and MmImp2 cDNAs were generated by introducing an in frame XbaI restriction site into the 3' end of the coding regions by PCR, effectively removing the stop codon of each cDNA.
To generate yeast mutants lacking the IMP1 gene or the SOM1 gene, PCR-mediated gene disruption (Wach et al., 1997) was used with the plasmid pFA6a-HIS3MX6 as template. For the knockin strain, MmImp1 was first cloned into a vector in front of a HIS3 gene marker. This vector was then used for PCR-mediated gene disruption. Yeast plasmids Caspase-3-LacZ, pADH-(TRP1)-MIHA, and pGALL-(HIS3)-Diablo54-237 and empty vector controls have been described previously (Hawkins et al., 2001). pGALL-(HIS3)-Diablo1-237 was generated by subcloning full-length mouse DIABLO with XhoI and NotI into pGALL-(HIS3).
Strains of Saccharomyces cerevisiae were grown at 30°C on YPAD [2% (wt/vol) glucose, 1%(wt/vol) yeast extract, and 2% (wt/vol) peptone supplemented with adenine sulfate)], grown until late log phase, and harvested by centrifugation; or grown on solid media containing 2% agar in YPAD or YPEG [2% (vol/vol) ethanol, 2% (wt/vol) glycerol, 1%(wt/vol) yeast extract, and 2% (wt/vol) peptone) or YPGal (2% (wt/vol) galactose, 1%(wt/vol) yeast extract, and 2% (wt/vol) peptone supplemented with adenine sulfate].
To determine expression levels of the DIABLO constructs, cytosolic extracts of transformed yeast were prepared according to Cartwright et al. (1997) and analyzed by SDS-PAGE and immunoblotting.
To rupture the mitochondrial outer membrane in vivo, yeast cells were cultured transiently on media containing 120 mM acetic acid. Acetic acid is not metabolized by glucose-repressed yeast cells, enters cells in the protonated form, but, if the extracellular pH is lower than the intracellular pH, deprotonation leads to transient acidification of the cytosol and some rupture of the relatively fragile mitochondrial outer membrane (Ludovico et al., 2002).
Functional IAP Antagonism Assay
Transformations were performed as described previously (Hawkins et al., 2000) and grown in selective minimal media with glucose overnight, recovered, and washed three times in 10 mM Tris-HCl, pH 8.0, EDTA 1 mM (TE), and the cell suspensions were standardized (as determined from OD600). After incubation for 8 h at room temperature in selective minimal media containing galactose, pH 3.0, lacking or containing 20 mM acetic acid, yeast was recovered, washed once with TE, and resuspended in TE. The yeast suspensions were equalized, and 5-µl drops of serial fivefold dilutions were spotted onto selective minimal media containing either glucose (to repress expression of caspase 3 and DIABLO) or galactose (to induce their expression).
Preparation of Mitochondria and Protease Sensitivity
Mitochondria were isolated according to Daum et al. (1982). Osmotic shock treatment, to produce rupture the outer membrane in purified mitochondria, was as described by Glick et al. (1992b), and trypsin treatments were performed as described previously (Beilharz et al., 1998). Samples of mitochondrial protein (100 µg) were separated by Tris-glycine SDS-PAGE, and Western blots were carried out according to published methods (Lithgow et al., 1994; Beilharz et al., 1998; Sambrook and Russell, 2001).
Prediction of the Mitochondrial Targeting Sequence in DIABLO
The mitochondrial targeting sequences of hundreds of proteins are now known and are usually rich in positively charged residues and with tendencies to form two to three turns of a helix with amphipathic character (von Heijne, 1986). Predotar (http://www.inra.fr/predotar/) is a neural network predictor trained to find such extensions and predicts a high score (0.984) for the likelihood that the amino terminus of DIABLO is a mitochondrial (matrix) targeting sequence. MitoProtII (ftp://ftp.ens.fr/pub/molbio) calculates a probability for a protein being mitochondrial based on physicochemical properties, including a mesohydrophobicity score (Claros et al., 1995; Claros and Vincens, 1996). Mitoprot scores DIABLO as 98.99% likely to be a mitochondrial protein. We recently showed that a combined prediction from both Predotar and MitoprotII is an excellent indicator for mitochondrial location (Lucattini et al., 2004).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Isolation of mitochondria from yeast cells expressing preDIABLO showed that much of the precursor form of DIABLO had been processed (Figure 2). As in mammalian cells expressing DIABLO (Du et al., 2000; Verhagen et al., 2000), some unprocessed preDIABLO was still partially exposed on the mitochondrial surface, because it was degraded when mitochondria were incubated with trypsin. The processed form, however, was protected from trypsin cleavage within the organelle, as is an apparent processing intermediate. Consistent with this conclusion, when the outer membrane was ruptured by osmotic shock, processed DIABLO was degraded by trypsin, as was the intermembrane space protein cytochrome (Cyt) b2. Matrix-located proteins, such as the mitochondrial 70-kDa heat-shock protein (mtHSP70) remained protected from trypsin by the inner mitochondrial membrane, even after the outer membrane was ruptured (Figure 2). The small fraction of DIABLO that is not degraded in this sample remains resistant to protease even in the presence of Triton X-100 (our unpublished data) that solubilizes the inner membrane, suggesting this fraction of the protein is aggregated into a protease inaccessible form. These experiments show that DIABLO is targeted by its amino terminal targeting sequence to the mitochondria, where the targeting peptide is removed liberating DIABLO in the intermembrane space.
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Processing of preDIABLO Is Required for Antagonism of IAP Function In Vivo
Mature DIABLO can antagonize the caspase inhibitory properties of MIHA in yeast (Hawkins et al., 2001), and we exploited this cellular system to explore the impact of the amino terminal region of DIABLO on its ability to antagonize IAP activity. Yeast tolerated expression of either the precursor or mature forms of DIABLO (Figure 3A, lanes 1 and 2). Expression of autoactivating caspase 3 was toxic (lane 3), unless inhibited by coexpression of MIHA (lane 4). Coexpression of the mature form of DIABLO [corresponding to DIABLO(54-237)] killed the cells due to liberation of active caspase 3 from MIHA (Figure 3A, lane 5).
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Yeast cells expressing the precursor form of DIABLO, which is targeted to mitochondria (Figure 1), together with autoactivating caspase 3 and MIHA survived (Figure 3B, lane 9) because the matured, active form is compartmentalized (within the mitochondrial intermembrane space) from MIHA and caspase 3. Nevertheless, rupturing the outer membrane of mitochondria by treatment of intact cells with 120 mM acetic acid (Ludovico et al., 2002) was able to antagonize the antiapoptotic effect of MIHA (Figure 3B, lanes 11 and 12). Because inhibition of MIHA requires the correctly processed AVPI amino terminus of DIABLO (Figure 3A, lane 6), preDIABLO must have been cleaved, in vivo, at the same processing site in yeast as it is in mammalian cells.
preDIABLO Is Processed by the IMP Complex
In yeast, few proteins have been identified that are proteolytically processed for release into the intermembrane space. The three best characterized, Cytb2, Cytc1, and Mcr1 (Gakh et al., 2002), each first dock with the TIM23 complex and are then processed by the IMP complex. The IMP complex is a hetero-oligomer integrated in the mitochondrial inner membrane, and deletion of any one subunit leads to destabilization and loss of the other subunits (Nunnari et al., 1993; Gakh et al., 2002). Two catalytic subunits, Imp1 and Imp2, are similar in sequence but seem to have nonoverlapping substrate specificities (Nunnari et al., 1993; Gakh et al., 2002). A third noncatalytic subunit, Som1 has been shown to assist substrate recognition by the catalytic Imp1 subunit (Esser et al., 1996; Jan et al., 2000). The oligomeric IMP complex processes mitochondrial presequences releasing matured proteins to the intermembrane space. To determine whether DIABLO is a substrate of the IMP complex, purified mitochondria of yeast strains expressing preDIABLO, but lacking one of the three subunits of the Imp complex, were assayed in Western blots for the presence or absence of the mature form of DIABLO (Figure 4).
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som1 mutants, processing to the mature form of Cytb2 occurred. The Imp1 subunit is primarily responsible for Cytb2 processing (Nunnari et al., 1993), and Figure 4 shows processing of Cytb2 is blocked completely in imp1 cells. Because yeast imp2 mutants express decreased levels of the Imp1 subunit (Nunnari et al., 1993), Cytb2 processing also is also blocked in imp2 cells. Analogously, processing of preDIABLO was partially compromised in imp2 mutants and failed to occur at all in either the imp1 and som1 mutants. We conclude the IMP complex processes preDIABLO to its mature form, and it is likely the Imp1 catalytic site at which this occurs.
Identification of Mouse Homologues for Yeast Imp1 and Imp2 Proteases
An IMP complex has not yet been functionally characterized in organisms other than S. cerevisiae. However, iterative BLAST analyses revealed genes predicted to encode proteins similar to Imp1 and Imp2 in all animals and fungi for which substantial genome sequence data exist (Figure 5). The catalytic serine and lysine residues and the structurally important arginine and aspartate residues from the yeast Imp1 and Imp2 (Chen et al., 1999) are conserved across all species (Figure 5, stars). In addition, we found a sequence motif that distinguishes Imp1(RX5P) from Imp2(NX5S). The sequence motif defining the Imp1 and Imp2 subunits sits close by structurally important aspartate residues thought to stabilize the shape of the substrate-binding cleft in the bacterial leader peptidase (Paetzel et al., 1998).
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) and MmImp2 localize to mitochondria (Figure 6A). Like yeast Imp1, MmImp1 could be stably expressed in imp1 yeast (Figure 6A) but not in wild-type (i.e., Imp1+) yeast cells (our unpublished data). The cytochrome substrates of the IMP complex are key components of the mitochondrial electron transport chain, so that neither imp1 mutants nor imp2 yeast mutants can grow on nonfermentable carbon sources. We exploited this phenotype to test for complementation, which would imply functional homology by the proposed mouse counterparts of the yeast IMP genes.
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imp2 strain, allowing it to process cytochromes and grow on the nonfermentable carbon sources ethanol and glycerol (Figure 6B). Based on sequence similarities, correct mitochondrial location and functional complementation, we suggest an IMP complex exists in mammalian cells for the processing and activation of proteins such as preDIABLO. That MmImp1 does not complement the growth defect of imp1 yeast cells (Figure 6B) suggests additional factors such as a mammalian homolog of Som1 might be needed for full activity of the MmImp1 subunit.
The loss of Imp2 destabilizes the IMP complex so that imp2 yeast cells process preDIABLO only poorly. However, this impairment was reversed by expression of MmImp2 in the imp2 yeast (Figure 6C). We conclude that preDIABLO is proteolytically activated to DIABLO by the IMP complex and that the mammalian Imp1 and Imp2 sequences represent functional homologues of the yeast IMP complex subunits.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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,b; van Loon and Schatz, 1987). The presequences of Cytb2 and Cytc1 resemble those in the targeting sequence of preDIABLO. A short region at the N terminus of preDIABLO is predicted to form a basic amphipathic helix that might direct the protein to the TIM23 complex (Figure 7B; see Materials and Methods). We have demonstrated that the final processing of DIABLO is carried out by the IMP complex, making its import pathway into mitochondria (Figure 7A) analogous to the stop-transfer pathway traveled by Cytb2 and Cytc1 (Glick et al., 1992a,b).
Imp1 and Imp2 are members of the signal peptidase family of proteases. In Escherichia coli, a signal peptidase removes the presequence of proteins translocated across the bacterial membrane (Paetzel et al., 2002). Two proteins related to the IMP subunits are present in all animals and fungi where complete genome information is available, and a diptych of amino acid residues corresponding to the motif RX5P in Imp1 and NX5S in Imp2 seems to be diagnostic for Imp1 or Imp2. The RX5P motif of Imp1 and its surrounding residues are conserved in the E. coli leader peptidase (Figure 5), and as part of a thorough examination of the structure of crystallized leader peptidase, Paetzel et al. (1998, 2002) suggested that arginine282 (in the RX5P motif) is important in stabilizing the active site region and positioning of surrounding amino acids). We note from their data that the proline288 residue seems to be involved in another structurally important position, in a turn between two beta-sheets (Strahm and Lithgow, unpublished observations). The distinguishing motif in Imp2(NX5S) and the context provided by surrounding residues might influence the structure around the active site enough to broaden the range of substrates that can be processed by the IMP complex. That the RX5P and NX5S sequence motifs are each so widely conserved through evolution shows they are fundamentally important for IMP complex activity and makes them the diagnostic motif in distinguishing Imp1 from Imp2.
Other Substrates of the Mammalian IMP Complex
A number of proteins that might potentiate apoptosis are released from mitochondria (van Gurp et al., 2003; Saelens et al., 2004). None of these have the hallmarks that would suggest activation by the IMP complex. A candidate substrate, AIF is a peripheral component of the mitochondrial inner membrane (Arnoult et al., 2002) made as a precursor protein, with a presequence of 101 residues processed after import into mitochondria (Susin et al., 1999). It is not clear yet which protease is responsible for AIF processing, but the presequence of AIF shows no obvious similarity to a stop-transfer sequence, and the processing site has none of the residues suggested to be important for recognition by the IMP complex (Gakh et al., 2002).
Cytochrome c is imported into the intermembrane space via the TOM complex without the participation of the TIM complex and without any proteolytic processing (Diekert et al., 2001; Wiedemann et al., 2003). HtrA2/Omi is targeted to the intermembrane space of mitochondria, but it is processed autocatalytically in mammalian cells (Seong et al., 2004) and in yeast (Verhagen and Silke, unpublished results), and its role in apoptosis might be secondary to its role as a molecular chaperone for other mitochondrial proteins (Vaux and Silke, 2003).
Endonuclease G (EndoG) is a mitochondrial protein, released during cell death, that contributes to nuclear DNA fragmentation in the terminal stages of apoptosis (Li et al., 2001). EndoG is encoded in the nucleus, translated as an 
33-kDa precursor in the cytosol, translocated across the mitochondrial membranes with the presequence and then cleaved to yield the 28-kDa mature nuclease (Schafer et al., 2004). EndoG had been tentatively suggested to be located in the intermembrane space (Ohsato et al., 2002), but EndoG must be located in the mitochondrial matrix for it to generate the primers needed for mitochondrial DNA replication (Cote and Ruiz-Carrillo, 1993) and would therefore be processed by matrix-located proteases (Gakh et al., 2002).
Discrete defects in mitochondrial protein import and sorting can lead to human disease. Mohr-Tranenberg syndrome, a deafness-dystonia disorder, results through mutations that effect assembly of the Tim8/Tim13 complex, thereby inhibiting protein sorting to the TIM22 complex (Roesch et al., 2002; Binder et al., 2003). Chromosomal mapping of patients suffering from Gilles de la Tourette syndrome, another neurological condition, has revealed that one of the genes located at a breakpoint region (7q31) that is associated with symptom development encodes the human ortholog of the protein we designate here as MmImp2 (Petek et al., 2001; Gakh et al., 2002). Speculation, based on sequence similarity the authors noted to the yeast Imp2, suggested that defects in respiratory chain complexes might impact on the etiology of Tourette syndrome and other neuropsychiatric disorders (Petek et al., 2001; Gakh et al., 2002). Our findings on the role of the IMP complex in processing non-cytochrome substrates such as DIABLO, suggest that if defects in the IMP complex contribute to Tourette syndrome and other conditions, it could be through downstream influences on cell development and function.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Footnotes |
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Abbreviations used: IAP, inhibitor of apoptosis protein; IMP, inner membrane peptidase; TIM23, translocase of the inner mitochondrial membrane; TOM, translocase of the outer mitochondrial membrane.
Address correspondence to: Trevor Lithgow (t.lithgow{at}unimelb.edu.au).
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