274 Journal of Atherosclerosis and Thrombosis Vol.18, No.4 ApoA-I Enhances Phagocytosis by Stabilizing ABCA7 275 Review

Roles of ATP-Binding Cassette Transporter A7 in Cholesterol and Host Defense System

Nobukiyo Tanaka, Sumiko Abe-Dohmae, Noriyuki Iwamoto, and Shinji Yokoyama

Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya Japan

ATP-binding cassette transporter (ABC) A7 is an ABC family that is a so-called full-size ABC transporter, highly homologous to ABCA1, which mediates the biogenesis of high-density lipo- protein (HDL) with cellular and helical apolipoproteins. ABCA7 mediates the formation of HDL when exogenously transfected and expressed; however, endogenous ABCA7 was shown to have no significant impact on the generation of HDL and was found to be associated with phagocytosis regulated by sterol regulatory element binding protein 2. Since phagocytosis is one of the fundamen- tal functions of animal cells as an important responsive reaction to infection, injury and , ABCA7 seems to be one of the key molecules linking sterol homeostasis and the host defense system. In this context, HDL apolipoproteins were shown to enhance phagocytosis by stabilizing ABCA7 against calpain-mediated degradation and increasing its activity, shedding light on a new aspect of the regulation of the host-defense system.

J Atheroscler Thromb, 2011; 18:274-281.

Key words; ABCA7, ApoA-I, HDL, Phagocytosis, ABCA1, Cholesterol

brane protein for cholesterol homeostasis, for the gen- Roles of ATP-Binding Cassette Transporter eration of HDL and the release of cell cholesterol for (ABC) A7 in cholesterol homeostasis its catabolism10). ABCA1 is one of the ABC family High-density lipoprotein (HDL) apolipopro- consisting of two sets of multiple membrane- teins, such as apolipoprotein (apo) A-Ⅰ and apoA-Ⅱ, spanning domains plus the Walker motifs for ATP in- are helical amphiphilic proteins bound to the HDL teraction11, 12), and is thereby classified as a so-called lipid surface in equilibrium with an aqueous phase. full-size ABC transporter. These helical apolipoproteins interact with the cell ABCA7 is another full-size ABC trans- surface in their free form and generate HDL particles porter showing the highest homology among those by removing cellular phospholipid and cholesterol1-3). known to human ABCA1 (54%) and human ABCA4 Fibroblasts from patients with , a ge- (49%)13). On the other hand, its interspecies identity netic HDL deficiency, lack the interaction with apoli- of the protein sequences is 79% between and poprotein4, 5) due to mutations in ABCA16-8), indicat- mice, less than that of ABCA1 (95%) and ABCA4 ing that this reaction is the main source of plasma (88%)14). Expression of the ABCA7 is regulated HDL. The reaction is one of the major pathways of by sterol regulatory element binding protein 215), in cellular cholesterol release along with diffusion-medi- an opposite direction to regulation of the ABCA1 ated nonspecific efflux9). Thus, ABCA1 is a key mem- gene by LXR with respect to induction by changes in the cellular sterol level16-18). ABCA1 mediated the pro- Address for correspondence: Nobukiyo Tanaka, Department of duction of HDL particles with cellular lipid and extra- Cardiovascular Medicine, Ichinomiya Nishi Hospital, Ichinomiya 1, 4) 494-0001, Japan cellular helical apolipoproteins . ABCA7 also medi- E-mail: [email protected] ated the formation of HDL when exogenously trans- Received: August 15, 2010 fected and expressed19-22), and the HDL particles gen- Accepted for publication: October 28, 2010 erated by ABCA7 possessed a smaller cholesterol/ 274 Journal of Atherosclerosis and Thrombosis Vol.18, No.4 ApoA-I Enhances Phagocytosis by Stabilizing ABCA7 275 Review

Table 1. Controversy over ABC transporters involved in phagocytosis Gene (alias) ABCA1 ABCA7 ABCC7 (CFTR) Structure (36) Number of 12 12 17 transmembrane helices Number of 2 2 2 binding domains Function Mendelian disorder Tangier disease, unknown , (pathological physiology) (Dysfunction of (Dysfunction of Cholesterol efflux) Chloride ion channel) (6, 7, 8) (33, 34) Regulation of Positive Positive Positive phagocytosis (28, 29) (15, 31) (32) Negative (30)

phospholipid ratio and small diameter on average23). ABCC7, the another function is chloride ion channel, However, endogenous ABCA7 was shown to have was reported as the cause of Cystic Fibrosis33, 34). no significant impact on the generation of HDL15, 24, 25). Phagocytosis of amine-coated latex beads triggered the No genetic defect was reported on the human ABCA7 proteolytic activation of sterol regulatory element gene. A high-density single nucleotide polymorphism binding protein-1a (SREBP-1a) and SREBP-2 with- (SNP) map of ABC transporters in Japan has been out lipid deprivation35), and phagocytosis induced constructed and 67 SNPs identified at the ABCA7 lo- ABCA7 up-regulation via SREBP2 activation under cus26), but no association has been indicated between similar experimental conditions15). the variations and pathological phenotypes. A homo- Structural 36) and functional characteristics of zygous ABCA7 knockout mouse was found to be em- ABCA1, ABCA7 and ABCC7 are summarized in Ta- bryonically lethal25) by one laboratory, but the other ble 1. group reported the generation of ABCA7 null mice24). Production of homozygous mice by intercrossing het- Subcellular localization of ABCA7 erozygotes was at the expected rate, and its develop- ment, including feeding behavior and weight gain up Overexpressed ABCA1 protein is localized main- to 10 weeks, was normal24). No marked phenotype ly in the plasma membrane37-39) consistent with the lo- was observed in these animals, except that the white calization of endogenous ABCA1 in the plasma mem- adipose tissue mass was about 50% less and the serum brane40). ABCA7 proteins resulting from transfected HDL cholesterol level was somewhat but significantly cDNA (wild type, GFP-tagged, and Flag-tagged) were lower than that of the wild-type control only in fe- found to be localized predominantly in the plasma males at the age of 10 weeks. No such change was de- membrane, but were also detected in the intracellular tected in male knockout mice24). The details of the membranes19, 20, 22, 25, 41). Probing cell surface protein roles of ABCA7 in cholesterol homeostasis are sum- by biotinylation of HEK 293 cells transfected with marized in the previous review23). ABCA7 cDNA confirmed the cell surface expression of the transfected and expressed ABCA7 protein20). In contrast, rat ABCA7 with no tag and with a GFP tag Role of ABCA7 in host defense systems at the N-terminus were both detected mainly in the Several ABC transporters, including ABCA1, plasma membrane when expressed in CHO cells, ABCA7, and ABCC7, were reported to relate to the while ABCA7 with GFP fusion to the C-terminus was phagocytic function of cells. Although ABCA1 is an localized by probing with the ABCA7 epitope and ortholog of C. elegans ced-7, a gene involved in the GFP fluorescence in the perinuclear membrane41). Im- phagocytosis of apoptotic cells27), both positive28, 29) munofluorescence microscopy analysis of non-perme- and negative regulation30) of cellular phagocytotic abilized cells with the antibody against the first puta- function by ABCA1 was observed. ABCA715, 31) and tive extracellular domain of human ABCA7 (amino ABCC732) were reported to be phagocytic potentiators. acids 45-549) confirmed the cell surface expression of 276 Tanaka et al. ApoA-I Enhances Phagocytosis by Stabilizing ABCA7 277

the overexpressed ABCA7 protein22). The latter exper- mediated degradation by helical apolipoproteins iment also revealed that this domain is exposed to the (Fig.1C)43). Thus, both ABCA7 and ABCA1 seem to outside of the cell, indicating the same topological ar- be processed essentially in a similar manner. rangement as ABCA137, 38, 42). On the other hand, im- munofluorescence confocal microscopy with rabbit Helical apolipoprotein-mediated stabilization anti-mouse ABCA7 antibody detected no signal of of ABCA7 and phagocytosis enhancement ABCA7 in the plasma membrane, but rather in the in- tracellular space in peritoneal macrophages25), or re- Effects of helical apolipoproteins on the stabiliza- distribution into phagocytosis cups duirng phagocyto- tion of ABCA7 and enhancement of phageocytosis sis31). Our previous study with immunofluorescent were examined43). Decay of ABCA7 protein examined probing indicated intracellular localization of endoge- in the presence of the protein synthesis inhibitor cy- mous ABCA715), however, estimation of cell surface cloheximide was retarded by apoA-Ⅰ and apoA-Ⅱ, ABCA7 in J774 and mouse fibroblasts by a biotinyl- similarly to the findings with ABCA1 (Fig.1C, upper ation technique directly demonstrated that endoge- panel)43). Calpeptin increased ABCA7 protein as well nous ABCA7 mainly existed in the plasma membrane as ABCA1 protein by retarding their decay rate and apoA-Ⅰ increased cell surface ABCA7 (Fig.1A)43). (Fig.1C, lower panel)43). This discrepancy may be consistent with the assump- ApoA-Ⅰ and apoA-Ⅱ enhanced phagocytosis tion that ABCA7 turns over rapidly on the cell sur- (Fig.1D)43). Expression of ABCA1 or ABCA7 was face. down-regulated by the respective siRNA in J774 and a quantitative phagocytosis assay was performed. Phagocytosis enhancement by apoA-Ⅰ and apoA-Ⅱ Glycosylation of ABCA7 was ablated in the cells by knockdown of ABCA7, but Exogenously transfected ABCA1-GFP in remained after knockdown of ABCA1 (Fig.1E)43). HEK293 cells was highly glycosylated37, 38). Peptide N Phagocytic activity of macrophages in the mouse peri- glucosidase F treatment revealed that ABCA244), toneal cavity in vivo was examined by measuring the ABCA345), and ABCA446) proteins were also glycosyl- uptake of carbon microparticles after injecting them ated. We therefore investigated the glycosylation of into the peritoneal cavity. Uptake of the particles by endogenous ABCA7 as well as ABCA1. The results in- peritoneal cells was decreased in ABCA7-knockout dicated that ABCA7 contains N-glycoside-linked oli- mice compared to wild-type mice (Fig.1F). Helical gosaccharides as ABCA1 (Fig.1B)43). This modifica- apolipoproteins are carried by HDL and may dissoci- tion of ABCA7 was not influenced by extracellular ate from lipoprotein particles in equilibrium52). It is apoA-Ⅰ43). not completely clear yet whether helical apolipopro- teins directly bind to ABCA1 or ABCA7 to achieve these effects20, 53), and it is still possible that ABC Turnover and degradation of ABCA7 transporters may be stabilized by alteration of the ABCA1 is stabilized against its calpain-mediated membrane microenvironment by modification of its degradation by helical apolipoproteins when the HDL lipid composition. biogenesis reaction is ongoing47-50). With the biotinyl- ation method, ABCA1 on the surface was shown to be Conclusion internalized and intracellularly degraded. Exposure of ABCA1 to extracellular apoA-I before its endocytosis This review is summarized in Table 2 and Fig.2. retarded ABCA1 internalization protected ABCA1 ABCA7 is highly homologous to ABCA1 and mainly against this calpain-mediated proteolysis and conse- exists in the plasma membrane, as does ABCA1. Its quently recycled more ABCA1 to the surface to in- post-transcriptional regulation, glycosylation and deg- crease surface ABCA1, perhaps by forming a complex radation are also quite similar to ABCA143); however, prior to endocytotic internalization for its intracellular the function of the two transporters is different. proteolysis51). Direct inhibition of ABCA1 endocyto- ABCA1 generates HDL with apolipoproteins, but en- sis also led to a decrease of its degradation and in- dogenous ABCA7 does not contribute to HDL bio- creased surface ABCA1. When HEK293 cells stably genesis. ABCA7 is rather involved in the enhancement expressing ABCA7-GFP were treated by N-acetyl- of phagocytosis, and apolipoproteins further increase Leu-Leu-norleucinal (ALLN) or apoA-Ⅰ, ABCA7 pro- this function43). tein increased19). Our recent study showed that endog- Contribution of HDL to the host defense system enous ABCA7 was also stabilized against its calpain- has been previously indicated as the inhibition of LPS. 276 Tanaka et al. ApoA-I Enhances Phagocytosis by Stabilizing ABCA7 277

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Fig.1. Phagocytic enhancement by stabilizing ABCA7 (A) ABCA7 is localized on the cell surface. After overnight incubation of J774 with apoA-Ⅰ, biotinylated (surface) and non- biotinylated (intracellular) proteins were prepared for Western blotting after the treatment of cells with 1 mM biotin. W in- dicates analysis of the whole cell lysate without biotinylation. (B) ABCA7 is glycosylated. After overnight incubation of J774 with apoA-Ⅰ, membrane proteins treated with each (Endoglycosidase H (endoH) or peptide: N-glycosidase F (PNGase F)) were analyzed by Western blotting. (C) ABCA7 is degradated by calpain, and is degradation is inhibited by helical apolipoproteins. (Upper panel) After overnight in- cubation of J774 with apoA-Ⅰ or apoA-Ⅱ, protein synthesis was inhibited by cycloheximide, and proteins were analyzed by West- ern blotting at 0, 3, 6 h of incubation. (Lower panel) After overnight starvation of J774 cells, the cells were preincubated with and without calpeptin for 1 h, and then incubated for 0, 3, or 6 hours under inhibition of protein synthesis by cycloheximide. (D) and (E) Helical apolipoproteins enhance phagocytosis through ABCA7. After overnight incubation with apoA-Ⅰ or apoA-Ⅱ of J774 (D) or J774 knocked-down ABCA7 and ABCA1 (E), a quantitative phagocytosis assay was performed. (F) Phagocytic function is attenuated in ABCA7-knockout mice. Diluted carbon ink was injected into the mouse peritoneal cavity. After overnight starvation of mice, peritoneal macrophages were recovered and over 400 cells were counted to calculate the phagocytosis index as a relative number of cells that engulfed carbon ink particles. Statistical analysis was performed to give significance levels as＊＊＊, p＜0.001 to the control or between groups is indicated. See reference 39 for detailed methods. 278 Tanaka et al. ApoA-I Enhances Phagocytosis by Stabilizing ABCA7 279

Table 2. Summary of findings ABCA1 ABCA7 Structure 12 transmembrane spans 12 transmembrane spans (12, 37) (12, 37) Localization Plasma membrane Plasma membrane (40) (43) Transcription LXR SREBP (16) (15) Glycosylation N-glycosylated N-glycosylated (37, 38) (43) Degradation Calpain Calpain (20, 49, 50, 51) (43) apoA-I-mediated Yes Yes stabilization (47, 49, 50, 51) (43) apoA-I-mediated Endogenous: Yes Endogenous: No HDL generation (4, 5) (15, 24, 25) Exogenous: Yes Exogenous: Yes (19, 21, 38, 42) (19, 20, 21, 22) apoA-I-mediated No Yes phagocytosis (43) (43)

Fig.2. Relationships among cholesterol homeostasis, HDL generation, and phagocytosis.

HDL traps LPS54, 55) and HDL apolipoproteins and tion to the host-defense system. The finding would amphiphilic α helical peptides block the uptake of provide new insight into the relationship between LPS through SR-BI50) as its competitive ligands. In- cholesterol homeostasis and phagocytosis in host de- volvement of ABCA7 in phagocytosis and its modula- fense systems. tion by helical apolipoproteins of HDL revealed a more direct molecular mechanism of HDL contribu- 278 Tanaka et al. ApoA-I Enhances Phagocytosis by Stabilizing ABCA7 279

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