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The ABC Half Transporter, ABCG4 Induces Apoptosis and Forms Heterodimer with ABCG1

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The ABC Half Transporter, ABCG4 Induces Apoptosis and Forms Heterodimer with ABCG1 The ABC half transporter, ABCG4 induces apoptosis and forms heterodimer with ABCG1 Zoltán Hegyi, Balázs Sarkadi, László Homolya Membrane Biology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary Introduction Figure 3. Functional ABCG4 induces apoptosis Since the morphological alterations observed in the ABCG4-expressing cells were indicative of apoptosis, The ABCG1 and ABCG4 proteins are members of the ATP binding cassette (ABC) transporter G subfamily. we examined phosphatidyl-serine (PS) translocation, an early apoptotic event in HEK293H cell lines Unlike most ABC transporters, the ABCG1 and ABCG4 proteins consist of only one nucleotide binding transiently transfected with the wt ABCG4 and its inactive mutant (KM) variant. PS translocation was domain (NBD) and one transmembrane domain (TMD), therefore are called ABC half-transporters. Some monitored by fluorescently labeled Annexin V binding (green). The total cell number was determined by members of the ABCG subfamily have proven to function as homodimers (ABCG2) or heterodimers nuclear staining by Hoechst (blue). (ABCG5/ABCG8). Previous results indicated potential heterodimerization between ABCG1 and ABCG4 (1). Regarding their function, ABCG1 has been proposed to play a role in cellular lipid/sterol regulation, whereas We found that the cultures transfected with wt ABCG4 contained a large number of cells exhibiting Annexin the function of ABCG4, the closest relative of ABCG1, is still elusive. Recently, we reported that functional V binding, whereas hardly any labeling for PS translocation was seen in cultures transfected with the KM expression of ABCG1 induces apoptosis in several cell types (2). Our finding was supported by rounded cell mutant. For comparison, Annexin V binding was also examined in cells transfected with the wt ABCG1, morphology, phosphatidyl-serine externalization, and elevated caspase 3 activity in the ABCG1-expressing ABCG1-KM, and ABCG2, respectively. The wt ABCG1 induced apoptosis to a greater extent than ABCG4, cultures. In the present work we have investigated the effect of functional expression of ABCG4 in several whereas no elevated apoptosis was seen in response to ABCG2 overexpression. cell lines and the homo- and heterodimer formation of these two proteins. HEK293H HEK293H out TMD in ABCG4 COOH NH2 NBD ABCG4-KM Figure 1. Expression of ABCG proteins in HEK cells HEK293H cells were transiently transfected with the vectors containing the wild type (wt) or an inactive mutant (KM) form of the ABCG subfamily members ABCG1, G2 and G4. 24 hours after transfection the cells were lysed in Laemmli sample buffer or fixed and permeabilized, and immunostained by an appropriate antibody. The expression and localization of the proteins were visualized by SDS-PAGE and confocal microscopy ABCG1 (Olympus FV500-IX). Here we demonstrate the results obtained using ABCG4-transfected cells using an anti- ABCG4 antibody, developed in our laboratory. As documented here, wt ABCG4 migrated at approximately 60kDa and induced changes in cell shape with characteristic ‘rounding up’ and detachment, whereas cells expressing the inactive KM mutant form of ABCG4 exhibited normal cell morphology. Figure 4. Functional cooperation between ABCG1 and ABCG4 ABCG4 ABCG4-KM parental ABCG4 The phenomenon of ABCG1- or ABCG4-induced apoptosis allows us to generate further support for the homodimerization and heterodimerization. The cells were co-transfected with wt ABCG1 or ABCG4 and 75- with 2-fold excess of various inactive mutant variants (G1-KM G4-KM, or G2-KM). Protein expression was verified by immunostaining. Both G1-KM and G4-KM greatly reduced the number of apoptotic cells in the co-transfected cultures, whereas G2-KM had no such effect. The observed dominant negative effects 50- strongly suggest a functional cooperation between ABCG1 and ABCG4, and supports the notion that both homo- and heterodimers can be formed. Annexin V Immunostaining G1 G1/G1-KM G1/G4-KM G1/G4-KM Figure 2. ABCG4 forms homodimer, and heterodimer with ABCG1 Recent studies showed similar expression patterns for ABCG1 and ABCG4 in the brain. This observation supports the hypothesis that these transporters may form heterodimers (3,4). ATPase activity measurements in our laboratory also implied heterodimerization (1). We were able to demonstrate the physical interaction between ABCG1 and ABCG4 by co-immunoprecipitation, using antibodies developed in our laboratory. In the homodimerization experiment, HEK293H cells were co-transfected with N-terminally GFP tagged G4/G4-KM G4 G4/G1-KM G4/G4-KM G4/G1-KM ABCG4 and 2-fold excess of wt ABCG4. For immunoprecipitation the cells were lysed in 0,5% NP-40 containing buffer and a rabbit anti-GFP antibody was used to immunoprecipitate GFP-ABCG4, and interaction partner, wt ABCG4. Heterodimerization studies were carried out as follows: HEK293H cells were co-transfected with wt ABCG4 and 2-fold excess of various forms of ABCG1 (wt or KM) or ABCG2-KM. An anti-ABCG4 antibody were used to immunoprecipitate ABCG4 and its interaction partners. Both the wt and the inactive forms of ABCG1 interacted with ABCG4, whereas G2-KM did not. These co-immunoprecipitation experiments confirmed the homodimer formation of ABCG4 and its heterodimerization with ABCG1. Annexin V anti-ABCG1 anti-ABCG4 IP: αGFP IP: αG4 HEK293H G2KM G1 G1/G4 G1KM G1KM/G4 G2KM/G4 G4 GFP-G4/G4 input input GFP-ABCG4 input αG1 75- αG2 75- ABCG4 αG4 ABCG1 50- αG4 Ab 50- αG4 Ab 75- GFP-ABCG4 HC HC ABCG4 input input 50- αG4 75- αG4 75- ABCG4 ABCG4 50- αG4 Ab 50- αG4 Ab HC HC Conclusion Functional ABCG4 expression induces apoptosis. ABCG1 and ABCG4 proteins can form both homo- and heterodimers. Acknowledgments References 1) Cserepes et al. (2004) Biochem Biophys Res Commun 320(3): 860-7 We appreciate the technical help of Gyöngyi Bézsenyi. This work was supported by the research grants from OTKA (K68936, 2) Seres et al. (2008) Biochim Biophys Act 1778(10): 2378-87 CK 80283), ETT (211-09), National Development Agency KMOP-1.1.2-07/1-2008-0003, and Gedeon Richter Inc. 3) Tarr and Edwards (2008) J Lipid Res 49(1): 169-82 • 4) Wang et al. (2008) FASEB J 22(4):1073-82.
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