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Cytosolic Signaling Protein Ecsit Also Localizes to Mitochondria Where It Interacts with Chaperone NDUFAF1 and Functions in Complex I Assembly

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Cytosolic Signaling Protein Ecsit Also Localizes to Mitochondria Where It Interacts with Chaperone NDUFAF1 and Functions in Complex I Assembly Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly Rutger O. Vogel,1 Rolf J.R.J. Janssen,1 Mariël A.M. van den Brand,1 Cindy E.J. Dieteren,1,2 Sjoerd Verkaart,2 Werner J.H. Koopman,2 Peter H.G.M. Willems,2 Wendy Pluk,1,3 Lambert P.W.J. van den Heuvel,1,3 Jan A.M. Smeitink,1 and Leo G.J. Nijtmans1,4 1Department of Paediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands; 2Department of Membrane Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands; 3Nijmegen Proteomics Facility, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands Ecsit is a cytosolic adaptor protein essential for inflammatory response and embryonic development via the Toll-like and BMP (bone morphogenetic protein) signal transduction pathways, respectively. Here, we demonstrate a mitochondrial function for Ecsit (an evolutionary conserved signaling intermediate in Toll pathways) in the assembly of mitochondrial complex I (NADH:ubiquinone oxidoreductase). An N-terminal targeting signal directs Ecsit to mitochondria, where it interacts with assembly chaperone NDUFAF1 in 500- to 850-kDa complexes as demonstrated by affinity purification and vice versa RNA interference (RNAi) knockdowns. In addition, Ecsit knockdown results in severely impaired complex I assembly and disturbed mitochondrial function. These findings support a function for Ecsit in the assembly or stability of mitochondrial complex I, possibly linking assembly of oxidative phosphorylation complexes to inflammatory response and embryonic development. [Keywords: Mitochondria; oxidative phosphorylation; complex I; NADH:ubiquinone oxidoreductase; Ecsit; NDUFAF1] Supplemental material is available at http://www.genesdev.org. Received September 5, 2006; revised version accepted January 22, 2007. Regulation of gene expression is one of the cornerstones rides) to activate expression of NF-␬B and AP-1 transcrip- of biological versatility. It is achieved by feedback tion factors, which in turn, activate expression of genes mechanisms between different subcellular pathways, of- involved in the immune response (Medzhitov et al. ten mediated by regulatory adaptor proteins. In 1999, 1997). Signal transduction can occur in two ways: either Kopp et al. (1999) described a prominent example of such via TAK1 and regulators TAB1 and TAB2, or via MEKK1 a protein, termed Ecsit (an evolutionary conserved sig- and subsequent MKK activation (Moustakas and Heldin naling intermediate in Toll pathways). Ecsit is a cyto- 2003). Communication between the two cascades is pos- plasmic signaling protein that constitutes a molecular sible, as TAK1 can activate MKKs and their downstream link between two pathways: the Toll signaling pathway effectors and MEKK1 can activate the TAK1-activated and the BMP pathway. IKK complex. TRAF6 (tumor necrosis factor [TNF] re- The family of Toll-like receptors (TLRs) consists of ceptor-associated factor 6) is an early component of both 10–15 members in most mammalian species, sharing a cascades, and yeast two hybrid and immunoprecipitation conserved Toll/IL-1 receptor (TIR) domain (Sims et al. studies have shown the association of Ecsit with TRAF6, 1988; Greenfeder et al. 1995; Medzhitov et al. 1997; To- thereby directly linking the protein to the Toll pathway rigoe et al. 1997; Chaudhary et al. 1998; Rock et al. 1998; (Kopp et al. 1999). In addition, Ecsit interacts with and Iwasaki and Medzhitov 2004). TLRs bind extracellular may facilitate processing of MEKK-1, findings that have ligands (e.g., Gram-negative bacterial lipopolysaccha- placed Ecsit in an immunological context. In 2003, Xiao et al. (2003) found an additional role for this protein in the BMP (bone morphogenetic protein) pathway in mouse embryogenesis. Null mutation of the 4Corresponding author. E-MAIL [email protected]; FAX 31-24-3618900. Ecsit gene in mice resulted in embryonic lethality with Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.408407. phenotypes that mimic those of a BMP receptor gene GENES & DEVELOPMENT 21:615–624 © 2007 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/07; www.genesdev.org 615 Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Vogel et al. (Bmpr1a)-null mutant (reduced epiblast cell prolifera- 1999; Xiao et al. 2003). Ten Ecsit splice isoforms are tion, block of mesoderm formation, and embryonic le- predicted, of which only isoforms 1 and 2 have been an- thality at the beginning of gastrulation). Bmp4 is known notated and encode proteins with predicted molecular to play an essential role in the gastrulation of the mouse masses of 50 and 33 kDa, respectively (Fig. 1A). Analysis embryo and signals through Bmpr1a, a type I Bmp recep- of the TAP purified peptides reveals the presence of the tor to induce up-regulation of target genes including peptide DSTGAADPPQPHIVGIQSPDQQAALAR, which Tlx2, a homeobox gene (Tang et al. 1998). Ecsit2 associ- crosses the boundary between exons 5 and 6, and thereby ates constitutively with Smad4, and associates with identifies the largest, 50 kDa Ecsit isoform 1 (Fig. 1B; Smad1 in a Bmp-inducible manner. Furthermore, to- Supplementary Table 2). gether with Smad1 and Smad4, it binds to the promoter of specific Bmp target genes (Xiao et al. 2003). Confirma- Ecsit localizes to mitochondria tive of its role in the Toll signaling pathway, short hair- pin RNA (shRNA) inhibition of Ecsit in a macrophage The interaction between NDUFAF1 and Ecsit is unex- cell line resulted in drastic inhibition of LPS-induced pected, since NDUFAF1 is described to be mitochon- NF-␬B activity (Xiao et al. 2003). This demonstrated that drial, whereas Ecsit is described as a cytoplasmic protein. both the BMP and Toll signaling pathways require Ecsit, However, although a mitochondrial function for Ecsit which herewith represents a link between immunity and has not yet been described in the literature, all tested embryonic development. mitochondrial targeting sequence prediction programs In this study, we show an unexpected additional func- (MitoPROT2, TargetP, Predotar, SignalP) clearly indicate tion for Ecsit in mitochondria, to which it is targeted by a mitochondrial targeting sequence with high probabil- an N-terminal targeting sequence and where it interacts ity. MitoPROT2 predicts a 99.3% chance of a cleavable with NDUFAF1, a chaperone involved in assembly of N-terminal target sequence of 49 amino acids, corre- mitochondrial complex I (NADH:ubiquinone oxidore- sponding to ∼5 kDa. ductase) (Janssen et al. 2002; Vogel et al. 2005). Complex To verify these predictions, we have performed frac- I is one of the five enzymatic complexes that comprise tionations of HEK293 cells to separate mitochondria the oxidative phosphorylation (OXPHOS) system in the from other cellular compartments. Figure 2A shows pre- mitochondrial inner membrane, responsible for the gen- dominant immunodetection of 50-kDa Ecsit isoform 1 in eration of ATP from NADH and FADH2 (Brandt 2006; the cytoplasm/nucleus, in line with its previously de- Janssen et al. 2006). Ecsit knockdown using RNA inter- scribed cytoplasmic function (Kopp et al. 1999; Xiao et ference (RNAi) results in decreased NDUFAF1 and com- al. 2003). In contrast to the cytoplasmic fraction, an ∼45- plex I protein levels, accumulation of complex I subcom- kDa Ecsit signal is specifically observed in mitochondria plexes, and disturbed mitochondrial function. Herewith, (Fig. 2A). As controls, Ecsit-binding partners TRAF6 and in addition to its cytoplasmic and nuclear functions, GAPDH do not show presence in mitochondria and are these findings point toward a mitochondrial function for clearly cytoplasmic, and mitochondrial complex IV sub- Ecsit, and could provide a link between mitochondrial unit COXII localizes in mitochondria. OXPHOS system biogenesis and function, immune re- To confirm the mitochondrial localization of the 45- sponse, and mesoderm formation during embryogenesis. kDa Ecsit, we have performed trypsin digestion of mito- chondrial outer membrane proteins (Fig. 2B). After cell Results fractionation, performed as for Figure 2A, mitochondria were treated for 15 min at 37°C with either 30 U of Ecsit copurifies with OXPHOS assembly trypsin, 100 U of trypsin, or 30 U of trypsin in the pres- chaperone NDUFAF1 ence of 1% Triton, which lyses the mitochondria and Mitochondrial ATP production occurs via the OXPHOS should thus result in complete degradation of all mito- system, which consists of five membrane-embedded pro- chondrial proteins. Increasingly, stringent trypsin treat- tein complexes (Janssen et al. 2006). The assembly pro- ment led to the degradation of the 50-kDa Ecsit, whereas cess of the largest of these, complex I, is a challenging the 45-kDa Ecsit was only degraded upon mitochondrial problem (Vogel et al. 2004). It is known to involve as- lysis. This suggests that the 45-kDa Ecsit is shielded by sembly chaperone NDUFAF1, but the mechanism of its the mitochondrial outer and inner membranes, and most action remains unclear (Janssen et al. 2002; Vogel et al. likely is imported into mitochondria. As controls, outer 2005). In order to find mitochondrial-binding partners for membrane
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