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A Novel Protein, RTN-Xs, Interacts with Both Bcl-Xl and Bcl-2 on Endoplasmic Reticulum and Reduces Their Anti-Apoptotic Activity

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A Novel Protein, RTN-Xs, Interacts with Both Bcl-Xl and Bcl-2 on Endoplasmic Reticulum and Reduces Their Anti-Apoptotic Activity Oncogene (2000) 19, 5736 ± 5746 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc A novel protein, RTN-xS, interacts with both Bcl-xL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity Shinji Tagami1,2,3, Yutaka Eguchi1,3, Manabu Kinoshita1, Masatoshi Takeda2 and Yoshihide Tsujimoto*,1,3 1Department of Medical Genetics, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan; 2Department of Neuropsychiatry, Osaka University Graduate School of Medicine, Osaka, Japan; 3CREST of Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Bcl-2 and Bcl-xL serve as critical inhibitors of apoptosis eects on the mitochondria, which play an essential triggered by a broad range of stimuli, mainly acting on role in apoptotic signal transduction (reviewed by the mitochondria. We identi®ed two members of the Green and Reed, 1998; Tsujimoto and Shimizu, 2000). reticulon (RTN) family as Bcl-xL binding proteins, i.e., Various apoptotic stimuli have been shown to induce NSP-C (RTN1-C) and a new family member, RTN-xS, mitochondrial changes that result in the release of both of which did not belong to the Bcl-2 family and apoptogenic factors like mitochondrial cytochrome c were predominantly localized on the endoplasmic (Liu et al., 1996) into the cytoplasm, which leads to reticulum (ER). RTN-xS interacted with both Bcl-xL activation of caspase-9 through Apaf-1 (Zou et al., and Bcl-2, increased the localization of Bcl-xL and Bcl-2 1997; Li et al., 1997). The release of cytochrome c is on the ER, and reduced the anti-apoptotic activity of prevented by anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2. On the other hand, NSP-C interacted (Yang et al., 1997; Kluck et al., 1997). Several eects only with Bcl-xL, aected the localization of Bcl-xL, and of them on the mitochondria have been proposed, such reduced Bcl-xL activity, but had no eect on Bcl-2. as closure of the voltage-dependent anion channel These results suggest that RTN family proteins can (VDAC) (Shimizu et al., 1999), the adenine nucleotide modulate the anti-apoptotic activity of Bcl-xL and Bcl-2 translocator (Marzo et al., 1998) or the permeability by binding with them and can change their localization to transition pore (Zamzami et al., 1996; Narita et al., the ER. Oncogene (2000) 19, 5736 ± 5746. 1998), as well as the binding and sequestration of Apaf-1 (Pan et al., 1998; Hu et al., 1998). Keywords: RTN-xS; Bcl-xL; Bcl-2; endoplasmic reticu- Although the eects of Bcl-2 on the mitochondria lum; apoptosis have been studied intensively, little is known about the eects of Bcl-2 on the endoplasmic reticulum (ER), where anti-apoptotic Bcl-2 family proteins are also Introduction localized. Bcl-xL and Bcl-2 regulate the release of calcium from intracellular stores, which are primarily Apoptosis plays an important role in a variety of located in the ER (Bay et al., 1993; Lam et al., 1994; biological events, including morphogenesis, mainte- He et al., 1997). It was also reported that Bcl-2 nance of tissue homeostasis, and removal of harmful targeted to the ER can inhibit Myc-induced apoptosis cells (reviewed by Kerr et al., 1972; Arends and Wyllie, (Zhu et al., 1996). These results suggest that Bcl-2 1991). Apoptotic signal transduction pathways acti- located on the ER might act to prevent apoptosis, vated by various stimuli converge into a phylogenically although the mechanisms involved are not clearly conserved common pathway, which is driven by understood. caspases and regulated by the Bcl-2 family (reviewed Bcl-xL and/or Bcl-2 are known to interact with by Salvesen and Dixit, 1997; Thornberry and Lazebnik, various proteins, such as pro-apoptotic Bcl-2 family 1998). Caspases are activated by proteolytic cleavage of members and other proteins from outside the Bcl-2 their proforms, and then cleave various cellular family. Among them, SMN (Iwahashi et al., 1997), Bis substrates (reviewed by Salvesen and Dixit, 1997; (Lee et al., 1999), and BAG-1 (Takayama et al., 1995) Thornberry and Lazebnik, 1998). are reported to enhance the anti-apoptotic eect of Bcl- The Bcl-2 family is characterized by the conservation 2. Bap31 (Ng et al., 1997), and SERCA (Kuo et al., of Bcl-2 homology (BH) domains (reviewed by Adams 1998) are localized on the ER, but their eects on the and Cory, 1998; Tsujimoto, 1998), and it consists of activity of Bcl-xL or Bcl-2 remain unknown. pro-apoptotic molecules (i.e. Bax, Bak, Bik, Bad, Bim The reticulon family gene 1 (RTN1) was identi®ed by and Bid) and anti-apoptotic molecules (i.e. Bcl-2, Bcl- antibodies that stained a subset of neuroendocrine xL, and Bcl-w) (reviewed by Adams and Cory, 1998; tissues and neoplasms (Roebroek et al., 1993), and was Tsujimoto, 1998). Recent studies have focused on their formerly called neuroendocrine-speci®c protein (NSP) gene. RTN1 produces three splice variants, which are designated NSP-A, -B, and -C. On the other hand, expression of its family genes, RTN2 and RTN3 is *Correspondence: Y Tsujimoto, Department of Medical Genetics, almost ubiquitous (Roebroek et al., 1998; Moreira et Biomedical Research center, Osaka University Graduate School of al., 1999). Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Received 24 July 2000; revised 13 September 2000; accepted 22 Immunohistochemical studies have revealed that September 2000 RTN proteins are anchored to the ER (Senden et al., Translocation of Bcl-xL and Bcl-2 to ER by RTN-xS S Tagami et al 5737 1996; GrandPre et al., 2000) probably through two residues, and lacked residues 186 to 1004 of RTN-xL putative transmembrane domains in the homologous (Figure 1a). The C-terminal amino acid sequence of C-terminal region, so these proteins were renamed the RTN-xS (aa 188 ± 373) shared 69% identity with that of reticulon (RTN) family (Roebroek et al., 1998). Little NSP-C (Figure 1b), and was the region where RTN is known about the function of the RTN family in family proteins showed signi®cant homology with each apoptosis. other (Roebroek et al., 1993, 1998; Moreira et al., Here we describe two Bcl-xL-interacting proteins 1999). RTN-xL and RTN-xS contained two putative belonging to the RTN family, NSP-C and a novel transmembrane domains, as do other RTN family member that we have termed RTN-xS. Unlike NSP-C, proteins (Figure 1b and Roebroek et al., 1993, 1998; RTN-xS can also interact with Bcl-2. RTN-xS reduced Moreira et al., 1999). the anti-apoptotic activity of both Bcl-xL and Bcl-2, Northern blot analysis revealed that the longest while NSP-C only reduced that of Bcl-xL. Change in transcript (about 5.4 kb) was speci®cally expressed in subcellular localization of Bcl-2 family proteins from brain and testis, as well as at low levels in heart and the mitochondria to the ER was thought to be involved skeletal muscle (Figure 2), consistent with RTN-xL in both cases. being isolated from the brain library. A transcript of about 3 kb should correspond to RTN-xS, because RTN-xS is 2457 bp shorter than RTN-xL. RTN-xS was expressed in all tissues examined, except for the liver Results (Figure 2). At least two other transcripts were observed in some tissues, but we did not characterize them. Identification of RTN-x S Northern blotting using NSP-C as a probe yielded To search for proteins interacting with Bcl-xL,we signals with dierent sizes from those obtained using screened human fetal and adult brain libraries using the RTN-x probe (data not shown). the yeast two-hybrid system, with full-length human Bcl-x as the bait. Fifty-seven b-galactosidase-positive L RTN-x interacts with both Bcl-x and Bcl-2 in clones were obtained from 26107 transformants, and S L mammalian cells were found to contain 19 bad, seven bax, three Bnip3L, and one bid gene, as well as 27 non-bcl-2 family clones. To examine the interaction of RTN-xL, RTN-xS, and Among the 27 clones, one clone carried the entire NSP-C with Bcl-xL or Bcl-2 in mammalian cells, N- coding sequence of NSP-C (RTN1-C) (Roebroek et al., terminal HA-tagged RTN-xL, RTN-xS, and NSP-C 1993) and two clones (4-20s and 15-97) corresponded expression plasmids were constructed (pCAGGS-HA- to a new member of the RTN family, which was RTN-xL, pCAGGS-HA-RTN-xS, and pCAGGS-HA- designated RTN-x. Analysis using the yeast two-hybrid NSP-C, respectively). We transiently co-transfected system revealed that both 4-20s and NSP-C bound to COS-7 cells with these plasmids together with Bcl-xL, but only 4-20s bound to Bcl-2 (Table 1). pCAGGS-Bcl-xL, pCAGGS-Bcl-2, or a control empty We obtained the full-length cDNA sequence of vector. Western blot analysis of immune complexes RTN-x as described in Materials and methods. There recovered with anti-HA serum revealed that both Bcl- were two kinds of cDNA, which may have been xL and Bcl-2 were co-immunoprecipitated with HA- produced by alternative splicing. The longer cDNA, RTN-xS only when co-expressed with HA-RTN-xS which we termed RTN-xL, contained 3576 bp encoding (Figure 3a,b). Identical results were obtained when 1192 amino acid residues, and was identical to the D98/AH2 cells were used instead of COS-7 cells (data human cDNA clone KIAA0886 in the DNA data base not shown).
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