1 Inserm, U682 Strasbourg, F67200, Development and Physiopathology of the Intestine and Pancreas, University Louis Pasteur, Strasbourg, France
2 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Pathologie Moléculaire, UPR 6520 CNRS/U596 INSERM, Université Louis Pasteur, BP10142, 67404 Illkirch, C.U. de Strasbourg, France
* Author for correspondence (e-mail: cat{at}igbmc.u-strasbg.fr)
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Summary |
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Key words: START, Cholesterol, Phosphatidylcholine, Lipid
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Introduction |
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In humans, START domains are found in 15 distinct proteins, either alone (in seven members of this family) or associated with other protein domains (in the remaining eight members) (Soccio and Breslow, 2003). The crystal structures of three of these have been solved, revealing a conserved `helix-grip' fold that forms an inner tunnel wide enough to accommodate the hydrophobic lipid (Roderick et al., 2002
; Tsujishita and Hurley, 2000
; Romanowski et al., 2002
). The identity of the lipids that bind each START domain is known for only a few members of the family, however. Recent work has implicated START proteins in the control of several aspects of lipid biology, including lipid trafficking, lipid metabolism and cell signaling. Moreover genetic, structural and functional studies are providing insight into the underlying mechanisms involved, as well as the distinct physiological and pathological roles of different START-domain-containing proteins. In this Commentary, we discuss these advances and the different models for START action that have been proposed. The evolution of the START domain has been discussed elsewhere (Soccio and Breslow, 2003
; Schrick et al., 2004
). We therefore focus here on the mammalian START proteins.
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Six START subfamilies in mammals |
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Disruption of the StAR gene in mice results in a similar disorder (Caron et al., 1997).
STARD3/MLN64
MLN64, like StAR, is a cholesterol-specific START protein. MLN64 was identified as a gene overexpressed in malignant compared with benign breast tumours (Tomasetto et al., 1995). It is overexpressed in about 25% of breast cancers (Bieche et al., 1996
; Kauraniemi et al., 2001
; Pollack et al., 2002
; Hyman et al., 2002
; Dressman et al., 2003
). MLN64 and StAR are differentially localized in cells (Fig. 3) (Clark et al., 1994
; Alpy et al., 2001
) but have similar biophysical and functional properties (Tuckey et al., 2004
). It may therefore be their expression patterns and subcellular localizations that distinguish them. The function of MLN64 remains elusive. The full-length protein has negligible steroidogenic activity, but a mutant containing only the START domain significantly promotes steroidogenesis by P450scc (Watari et al., 1997
) and can bind cholesterol at a 1:1 ratio (Tsujishita and Hurley, 2000
). MLN64 could thus function in steroidogenesis in organs that do not express StAR, such as the placenta (Watari et al., 1997
). However, mice lacking the MLN64 START domain appear normal and show no defect in steroidogenesis, making this unlikely (Kishida et al., 2004
).
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The STARD4 group
The related START-only proteins, STARD4, STARD5 and STARD6 were recently isolated by genomic studies after identification of STARD4 as an expressed sequence tag downregulated in mice maintained on a high-cholesterol diet (Soccio et al., 2002). Forced expression of STARD4 or STARD5 stimulates steroidogenesis by P450scc and liver X receptor reporter gene activity, thus indicating that both proteins function in cholesterol metabolism and might be cholesterol or sterol-specific binding proteins (Soccio et al., 2005
). Indeed, STARD5 was recently found to bind cholesterol and 25-hydroxycholesterol and no other sterols (Rodriguez-Agudo et al., 2005
). The lipid specificity of STARD6 is not known. STARD4 is induced by sterol-regulatory binding proteins and STARD5 expression is increased by endoplasmic reticulum stress (Soccio et al., 2005
). STARD5 is upregulated in lung cancers (Table 1). Although expressed in the same tissues, the STARD4 and STARD5 genes are differentially regulated, which suggests that they have distinct functions in cholesterol metabolism (Soccio et al., 2002
; Soccio et al., 2005
). By contrast, STARD6 is restricted to the testes and is expressed during spermatogenesis in spermatids but not in steroidogenic cells (Soccio and Breslow, 2003
; Gomes et al., 2004
). Because sterols and lipids play an important role in sperm function, and the plasma membrane cholesterol/phospholipid ratio falls during sperm capacitation (Travis and Kopf, 2002
), STARD6 might regulate lipid movement within the sperm cell membrane. Interestingly, STARD6 has been detected in the nucleus of mature rat sperm cells (Gomes et al., 2004
), where it could interact with transcriptional machinery in a lipid-dependent manner.
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The STARD2/PCTP group of lipid transporters of lipids
Phylogenetic analysis groups together phosphatidylcholine transfer protein, (PTCP, also known as STARD2), STARD7, STARD10 and STARD11 [also known as Goodpasture-antigen-binding protein (GPBP) or CERT]. This group is more heterogeneous than the others since the genes do not share common exonic organization and two of the proteins bind different lipids.
STARD2/PCTP
PCTP is a cytosolic lipid-specific transfer protein that promotes the rapid exchange of phosphatidycholine (PC) between membranes (Wirtz, 1991). PCTP-deficient mice appear normal (van Helvoort et al., 1999
), and the biological function of PCTP remains ill defined. It is believed to shuttle PC from its site of synthesis in the ER to the inner layer of the plasma membrane and/or the outer membrane of the mitochondria. This is thought to replenish plasma membrane with PC in response to phospholipid efflux during high-density lipoprotein (HDL) transport between tissues (Baez et al., 2002
; Baez et al., 2005
). Photobleaching experiments showed that PCTP is very mobile in the cytoplasm (de Brouwer et al., 2002
). Interestingly, in response to clofibrate treatment (a PPAR
agonist), PCTP becomes associated with mitochondria (de Brouwer et al., 2002
). This recruitment is associated with phosphorylation of the protein on serine 110, a conserved residue that is also phosphorylated in StAR (de Brouwer et al., 2002
). The precise role of this relocalization is unclear but suggests a potential mitochondrial function for PCTP (de Brouwer et al., 2002
).
STARD7
STARD7, also known as gestational trophoblastic tumour 1 (GTT1), was isolated as a gene overexpressed in choriocarcinoma (Durand et al., 2004). Its broad expression pattern indicates it might have a role in phospholipid transport. However, its common upregulation in many cancer-derived cell lines means it might play a role in phospholipid-mediated tumour signaling (Durand et al., 2004
). Unlike PCTP, its lipid specificity is not known.
STARD10
STARD10 (previously named PCTP-like) is widely expressed and synthesized constitutively in many organs, including liver, where it might act in export of lipids into bile. Recently, STARD10 was found to function as a phospholipid transfer protein by binding to phophatidylcholine and phosphatidylethanolamine (Oliayioye et al., 2005). STARD10 expression is also regulated during development in the testes and mammary glands (Yamanaka et al., 2000). The protein is concentrated in the sperm flagellum. Because enzymes involved in energy production are located in flagella and PC could be a potential substrate for this, STARD10 might play a role in energy metabolism by mobilizing PC (Yamanaka et al., 2000
). Interestingly, STARD10 and STARD6 show similar expression patterns in testes and may thus be partners in sperm cells. STARD10 expression is induced in mammary gland during gestation and lactation (Olayioye et al., 2004
). It is also upregulated in tumors from the mammary glands of transgenic mice expressing activated ErbB-2, a member of the epidermal growth factor (EGF) receptor family, and overexpressed in tumor-derived cell lines and 50% of ErbB-2-positive breast tumors (Olayioye et al., 2004
). The relationship between STARD10 and EGF receptors is unclear. However, in cotransfected NIH3T3 cell lines, STARD10 cooperates with ErbB-1 to promote anchorage-independent growth (Olayioye et al., 2004
).
PTCP, STARD7 and STARD10 are co-expressed in the liver, where they could function in the secretion of lipids into the bile. The absence of PTCP in mice does not impair PC secretion into bile (van Helvoort et al., 1999) possibly because this function is rescued by STARD7 and/or STARD10.
STARD11/CERT
STARD11, the only remaining START protein whose lipid specificity is known, is synthesized from two main transcripts: a long one encoding Goodpasture-antigen-binding protein (GPBP), also named CERTL; and a shorter one lacking one exon, GPBP26 (also known as CERT) (Raya et al., 2000
; Hanada et al., 2003
). The shorter transcript is the more abundant. In humans, STARD11 is expressed in many tissues, including skeletal muscle, heart, brain, kidney, pancreas and placenta (Raya et al., 2000
). STARD11 is composed of an N-terminal pleckstrin homology (PH) domain, a serine-rich motif, a potential coiled-coil region, a FFAT (two phenylalanine amino acids in an acidic tract) motif, a second 26-residue serine-rich motif (deleted in GPBP
26/CERT) and a C-terminal START domain. Recombinant STARD11 binds and phosphorylates Goodpasture antigen, the C-terminal region of the
3 chain of collagen IV, which is involved in the autoimmune disease Goodpasture disease (Raya et al., 1999
). The role of STARD11 in Goodpasture disease is unclear; however, it is expressed in cells and tissues targeted by the autoimmune response. STARD11 might phosphorylate Goodpasture antigen and trigger its processing and peptide presentation and thus mediate autoimmunity (Raya et al., 1999
; Raya et al., 2000
).
STARD11 was recently shown to act as a non-vesicular ceramide-carrier protein (Hanada et al., 2003). Ceramide is the precursor of sphingolipids, an abundant component of cell membranes. Ceramides are synthesized in the ER. They reach the Golgi apparatus by a major non-vesicular, ATP-dependent route and are then converted into sphingolipids. STARD11 rescues a mutant cell line that cannot transport ceramide from the ER to the Golgi (Hanada et al., 1998
; Hanada et al., 2003
). Distinct protein domains within the protein cooperate (Hanada et al., 2003
). The recently described FFAT motif binds to an ER membrane protein called vesicle-associated membrane-protein-associated protein (VAP) (Loewen et al., 2003
) and the PH domain targets STARD11 to the Golgi by interacting with phosphatidylinositol-4 monophosphate (Levine and Munro, 2002
). Deletion mutants reveal that only the START domain mediates ceramide transfer and is responsible for the specific exchange of ceramide from donor to acceptor membranes (Hanada et al., 2003
). STARD11 can efficiently transfer several natural ceramide species possessing long saturated acyl chains (C14-C20), C16-dihydroceramide and C16-phytoceramide (Kumagai et al., 2004
).
The RhoGAP START group
The RhoGAP START subfamily comprises deleted in liver cancer 1 (DLC-1, also known as STARD12 or p122), deleted in liver cancer 2 (DLC-2, also known as STARD13) and STARD8. Each has a Rho GTPase-activating protein (RhoGAP) domain and a C-terminal START domain. DLC-1 and DLC-2 each also possess an N-terminal sterile alpha motif (SAM) domain. The SAM domain is present in proteins involved in many biological processes and seems to have a variety of functions (Kim and Bowie, 2003), such as homo- and hetero-oligomerization, RNA binding and lipid binding (Barrera et al., 2003
). RhoGAP domains regulate the activity of Rho-family small GTPases by stimulating their inherent GTPase activity (Moon and Zheng, 2003
).
STARD12/DLC-1
The DLC-1 gene is a potential tumor suppressor gene located on chromosome 8 p21-22, a region of frequent loss of heterozygosity in human cancers (Yuan et al., 1998). It is deleted in liver and breast primary tumors (Yuan et al., 1998
; Yuan et al., 2003b
; Wong et al., 2003
) and downregulated in human liver, breast, colon and prostate cancer cell lines (Yuan et al., 2003a
; Plaumann et al., 2003
). Expression of DLC-1 in cell lines derived from liver, lung and breast carcinomas inhibits cell growth, colony formation and tumorigenicity in nude mice (Ng et al., 2000
; Yuan et al., 2003b
; Yuan et al., 2004
; Zhou et al., 2004
; Plaumann et al., 2003
). DLC-1 is a bi-functional protein. First, it interacts with PLC-
1 in vivo and stimulates hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns (4,5)P2], generating inositol 1,4,5-triphosphate and thus Ca2+ release from intracellular stores (Homma and Emori, 1995
). This activity depends on the C-terminal half of DLC-1, which encompasses the GAP and START domains (Sekimata et al., 1999
). Second, DLC-1 stimulates the intrinsic GTPase activity of RhoA, but not of Rac1, K-Ras, Rab3 or Cdc42Hs (Homma and Emori, 1995
). Expression of DLC-1 changes cell shape by inducing cell rounding and disassembly of stress fibers in a GAP-dependent manner. These morphological modifications are regulated by Rho GTPases (Sekimata et al., 1999
).
Rat DLC-1 localizes to the plasma membrane in caveolae, where it interacts with caveolin-1 (Yamaga et al., 2004), and in focal adhesions where it colocalizes with vinculin at the tips of actin stress fibers (Kawai et al., 2004
). The GAP domain alone is sufficient to localize DLC-1 to caveolae (Yamaga et al., 2004
), whereas the N-terminal part of the protein including the SAM domain targets it to focal adhesions (Kawai et al., 2004
). The DLC-1 knockout is lethal. Embryonic fibroblasts derived from DLC-1-deficient mouse embryos display alterations in the organization of actin filaments and focal adhesions, emphasizing its essential function in the cytoskeleton (Durkin et al., 2005
). Indeed, DLC-1 inactivation might contribute to the changes in cytoskeletal organization commonly found in cancer cells.
STARD13/DLC-2
DLC-2 is another potential tumor suppressor gene (located on chromosome 13q12.3) (Ching et al., 2003). Indeed, loss of its chromosomal region is common in hepatocellular carcinomas (HCC) and other cancers. DLC-2 is widely expressed, and the recombinant protein has GAP activity towards RhoA, Cdc42 and, to a lesser extent, Rac1 (Ching et al., 2003
; Nagaraja and Kandpal, 2004
). Its GAP domain can inhibit Rho-mediated cytoskeletal reorganization and stress fiber formation, which indicates that DLC-2 acts as a RhoGAP in vivo (Ching et al., 2003
; Nagaraja and Kandpal, 2004
).
STARD8
STARD8 lacks the N-terminal SAM domain present in the other member of this subfamily. Again it is widely expressed and downregulated in certain cancers (Table 1).
The sequences of DLC-1, DLC-2 and STARD8 are very similar, sharing >50% identity. All three are probably involved in cytoskeletal organization. In this subfamily, the START domain could have a regulatory role that is dependent on lipid.
The thioesterase START group
Brown fat-inducible thioesterase (BFIT, also known as STARD14) and cytoplasmic acetyl-CoA hydrolase (CACH, also known as STARD15) both contain two N-terminal acyl-CoA hydrolase domains and a C-terminal START domain (Fig. 1). They are serine esterases that have an active serine residue in the catalytic site and are similar to prokaryotic acyl-CoA thioesterases. BFIT hydrolyses medium- (C12-CoA) and long-chain (C16-CoA) fatty acyl-CoA substrates (Adams et al., 2001). CACH preferentially hydrolyses acetyl-CoA (Prass et al., 1980
; Suematsu et al., 2001
).
STARD14/BFIT
BFIT is induced in the brown adipose tissue of cold-challenged animals and repressed in animals at warmer temperatures (Adams et al., 2001), although it is widely expressed in humans. Two splice variants have been described: BFIT1 (607 amino acids) and BFIT2 (594 amino acids), which differ at their C-termini. This difference may affect the START domain since only BFIT2 possesses the C-terminal
4 helix found in other START proteins. Significantly, mice only have the BFIT2 isoform (Adams et al., 2001
).
Mouse BFIT is located in the genomic region containing the dietary-obese 1 (Do1) locus, which includes gene(s) potentially involved in body fat control. BFIT is more highly expressed in the brown adipose tissue of obesity-prone compared with obesity-resistant or lean mice (Adams et al., 2001). Interestingly, the chromosomal region containing the human BFIT gene is linked to body mass index and fat mass (Adams et al., 2001
). Given its expression pattern and enzymatic activity, BFIT probably has an important function in lipid metabolism.
STARD15/CACH
In mice, CACH expression is restricted to certain organs, including the liver, kidney, spleen, muscle and testes (NCBI UniGene EST Profile Viewer). This enzyme is only active as homodimers or tetramers (Isohashi et al., 1983b) and is allosterically activated by ATP and inhibited by ADP (Isohashi et al., 1983a
). Strikingly, CACH activity increases in opposing metabolic states, such as fatty acid synthesis and degradation (ß-oxidation) (Matsunaga et al., 1985
). Moreover, CACH has been linked to cholesterol metabolism, because its activity increases when cholesterol synthesis is inhibited (by chemical agents) or reduced (by high-cholesterol diets) (Ebisuno et al., 1988
). Given its preference for acetyl-CoA, CACH probably acts to maintain the equilibrium between cytoplasmic acetyl-CoA and CoA-SH available for fatty acids and cholesterol metabolism.
STARD9
Very little is known about STARD9. It is predicted to encode a large, >1820 residues protein containing a C-terminal START motif (Fig. 1). Besides the START domain, no other known region has been identified within its open reading frame.
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The 3D structure of the START domain |
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Ligand specificity |
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Lipid sensing |
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The function of RhoGAP START proteins might be regulated by the START domain in a lipid-dependent manner. Structurally, the RhoGAP START proteins resemble chimaerin proteins, which contain a RacGAP domain and a lipid-binding domain specific for diacylglycerol/phorbol-ester, the C1 domain (Brose and Rosenmund, 2002). Binding of phospholipids causes chimaerins to translocate to the Golgi apparatus and plasma membrane, and alters the conformation of the protein, allowing activation of the GAP domain (Canagarajah et al., 2004
). The RhoGAP START proteins might operate similarly, modulating the activity of RhoGAP and SAM domains in a lipid-dependent manner.
Similarly, within the thioesterase START group, the START domain could function as a lipid-sensing domain, providing a rapid way of regulating the catalytic activity of BFIT and CACH, and thus modulate lipid metabolism.
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Mechanism of lipid exchange |
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Surprisingly, impairing targeting of StAR to mitochondria by removing the 62 N-terminal residues has no effect on steroidogenesis monitored in vitro (Arakane et al., 1996). Moreover, StAR is inactive when trapped in the inner mitochondrial matrix or at the inner mitochondrial membrane (Bose et al., 2002
). In addition, biophysical studies of the N-terminally deleted forms of StAR have determined that StAR has a molten globule structure at low pH in solution and in association with membranes, and that the transition to this state is associated with cholesterol release (Bose et al., 2000
; Christensen et al., 2001
). Other analyses have shown that the
4 helix of the START domain of StAR can bind to synthetic membranes in a pH-dependent manner (Yaworsky et al., 2005
). Together, these data support the second model, indicating that StAR acts at the surface of the outer mitochondrial membrane. Upon interaction with the outer mitochondrial membrane, contact between the
4 helix of the START domain and acidic phospholipid heads might change the conformation of the protein and open the
4 `lid' to allow delivery (Fig. 4). Import of StAR into the mitochondrial matrix thus appears secondary to its action in steroidogenesis and instead probably terminates steroidogenesis (Bose et al., 2002
; Granot et al., 2003
).
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Intracellular contact sites between different membranes have been seen by microscopy (Holthuis and Levine, 2005). STARD11, using its FFAT and PH domains at the same time, could draw together components of the ER and Golgi. In this scenario, the START domain could extract and deliver ceramide by a flipping mechanism (Munro, 2003
). Similarly, in transfected cells, MLN64-containing late endosomal tubules align parallel to StAR-labeled mitochondria and transiently contact these (Zhang et al., 2002
). As shown in Fig. 4B, the MENTAL domain of MLN64 anchors the protein at the periphery of late endosomes, it also may capture cholesterol within the late endosome membranes, and the cytoplasmic START domain could extract cholesterol prior to its transfer to an acceptor membrane (Fig. 4B).
The recruitment of START proteins to specific contact sites would reconcile two contrasting observations about the function of the START domain: it binds only 1 mole of ligand per mole of protein but must handle several ligand molecules in a very short time. Indeed, StAR transfers over 400 molecules of cholesterol/StAR/minute (Artemenko et al., 2001). If acceptor and donor sites are brought together, one START protein could mediate such a rapid and efficient exchange of many ligand molecules.
To date, only membranes have been identified as lipid-exchange partners for START proteins. However START proteins might exchange lipids with acceptor proteins.
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Conclusions and perspectives |
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Some of the START proteins, such as StAR, are extremely well studied, whereas others, such as STARD8 or STARD9, remain largely uncharacterized. Identification of the ligand specificities and affinities, expression pattern and subcellular localization will be important if we are to understand their functions. In addition, it will reveal how generally applicable the model of START function we favor is to all members of the family.
Another important area of investigation is the role of these proteins in disease. The importance of mutations in StAR in lipoid CAH is evident and STARD11 might be implicated in autoimmune pathogenesis. However, the frequent overexpression or loss of START proteins in cancer cells means that the tumor promoting and tumor-suppressor roles of this interesting family should be further explored.
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Acknowledgments |
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References |
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