Gc-Globulin: roles in response to injury.
One of the intriguing properties of Gc-globulin is its ability to bind extracellular actin released by necrotic cell destruction into the circulation and, thus, to protect against disseminated intravascular coagulation induced by polymerized forms of actin (2). In this review we summarize the synthesis, structure and variants, multiple functional roles, analytical aspects, clinical relevance, and applications of Gc-globulin and of the actin-scavenging system.
Synthesis, Structure, and Variants
The Gc-globulin gene is expressed in a wide variety of tissues (3), and the protein is present in various body fluids (1). The vast majority of serum Gc-globulin is derived from expression and secretion by liver parenchymal cells, but minor contributions by nonhepatic cell types and nonparenchymal liver cells (our unpublished observation) exist. Gc-globulin has also been shown to be attached to the surface of a large number of cells (4), although they do not produce it. Together with the genes that encode albumin, [alpha]-fetoprotein, and the tocopherol-binding protein afamin, the Gc-globulin gene is located on chromosome 4, sublocalized to bands 4q11-q13. Gc-globulin contains 458 amino acids, folded into a disulfide-bonded, triple-domain structure divided into 2 repeated, homologous domains of 186 amino acids (domains I and II) and a shorter domain of 86 residues at the COOH terminus (domain III). Two binding regions have been identified within the sequence: a vitamin D-binding domain localized between residues 35 and 49 (domain I) and an actin-binding domain between residues 373 and 403 (domains II and III). The actin-binding site does not appear to interact significantly with vitamin D binding (5). Currently, it is not known in detail whether the binding capacity and/or affinity of Gc-globulin for G-actin is influenced by the loading with vitamin D and its metabolites. The actin-scavenging characteristics of Gc-globulin therefore cannot be predicted from the transport function of this protein in vitamin D metabolism. Only a minority of 5% of total plasma Gc-globulin is occupied by vitamin D, leaving the majority free for scavenger functions (1).
There are 3 codominant isoforms of full-length Gc-globulin, known as Gc1s, Gc1f, and Gc2, which differ by amino acid substitutions and glycosylation patterns (6). In addition to these 3 common isoforms, more than 120 genetic variants have been described. Gc2 is most prevalent among Caucasians but is rare in Africans, whereas the opposite is true for Gc1f. Gc-globulin variants are associated with different plasma concentrations of Gc-globulin, being relatively highest in Gc1-1 (Gc1s-1s, Gc1s-1f, and Gc1f-1f), intermediate in Gc1-2 (Gcls-2 and Gc1f-2), and lowest in Gc2-2 (7).
[FIGURE 1 OMITTED]
The function of Gc-globulin in trauma is associated with its role as an actin-scavenging protein in the vascular and extracellular system (Fig. 1). To date, Gc-globulin has been recognized widely as a protein with markedly decreased concentrations in inflammatory and necrotic diseases.
Actins are highly conserved proteins that are part of the cytoskeleton. They are involved in cell motility and in maintenance of cell shape. The intracellular proteins are released into the systemic circulation after disruption of the cell membrane as a result of necrosis. In the plasma, actin can form long filaments (F-actin) together with coagulation factor Va, a condition that triggers disseminated intravascular coagulation if not rapidly resolved. Decompensation leads to a condition resembling multiple organ dysfunction syndrome (MODS) (8). Thus, a complex actin-scavenging system has evolved in the vascular compartment, which involves 2 proteins: Gc-globulin and gelsolin (Fig. 1). Gc-globulin binds to monomeric G-actin, which is released by the action of gelsolin, a protein composed of 6 homologous domains (G1-G6). During the scavenging process, both G-actin-gelsolin and G-actin-Gc-globulin complexes are formed and subsequently cleared by the reticuloendothelial system much more efficiently than the free proteins, which have half-lives of ~1 day (Gc-globulin) and 2 days (gelsolin), respectively. Studies in animals have revealed that the half-life of G-actin-Gc-globulin complex in vivo is ~30 min. The net result is that both gelsolin and Gc-globulin are consumed (9). The plasma concentrations of Gc-globulin and gelsolin in a rat burn model (10) and in gelsolin-deficient mice (11) resemble those after severe injury. The finding that admission concentrations of gelsolin are also decreased in traumatized patients was supported in a study focusing on the role of gelsolin and the development of acute respiratory distress syndrome (ARDS) (12).
Low total and actin-free Gc-globulin concentrations, the latter being an index of residual actin-scavenging capacity, have been demonstrated to be prognostic markers in situations of severe organ damage, such as fulminant hepatic failure (13,14), acetaminophen (paracetamol) overdose (15), multiple trauma (16), and multiple organ failure (8,17). Other clinical situations such as septic conditions have also been shown to be associated with low Gc-globulin concentrations and actin complexation (16), but the specific role of Gc-globulin has yet to be defined.
Actin participates in many protein-protein interactions, including self-association of actin to form F-actin. A hydrophobic cleft between actin subdomains 1 and 3 is a "hot spot" for actin-binding proteins. Gc-globulin, F-actin, gelsolin, and ciboulot, a Wiskott-Aldrich syndrome protein family member, contain a-helices that are characterized by the presence of exposed and conserved hydrophobic side chains that bind in the cleft of actin. This cleft has global hydrophobicity. A hydrophobic pocket in subdomain 1, located at the entrance of the hydrophobic cleft, appears to be a primary target for both G-actin- and F-actin-binding proteins, including Gc-globulin (18).
Gelsolin ([M.sub.r] 85 000) is an actin-binding protein that is primarily involved in gel-to-sol transformations. Gelsolin exists in cytoplasmic and secreted forms (19). The skeletal muscle is the primary source of plasma gelsolin, although a gelsolin-like protein is also secreted by macrophages (20) (Fig. 1).
In the presence of [Ca.sup.2+], gelsolin severs and caps polymeric actin filaments (F-actin) (21): after binding of domain G1 and partly domain G2 to the actin filament (F-actin), gelsolin rapidly severs F-actin and then remains bound to the barbed end of one of the newly formed filaments, forming a stable cap, thus inhibiting addition of further monomers. The resulting G-actin monomers are bound by Gc-globulin, which releases gelsolin from actin. Severing and capping are additionally regulated by specific interactions between gelsolin and polyphosphoinositides, which inhibit binding to actin (22).
The concentration of gelsolin seems to be rate limiting in the actin removal system and depends on the rates of formation, dissociation, and clearance of the actin-gelsolin complex.
Functions Other than Actin Scavenging
In addition to scavenging of actin, Gc-globulin also plays additional roles in some non-actin-scavenging functions (Fig. 2.).
GC-GLOBULIN AS A TRANSPORTER FOR VITAMIN D AND ENDOTOXIN
Gc-globulin is a key component in the operation of vitamin D metabolism. It binds vitamin D and vitamin D analogs with different affinities at a binding site located in the N-terminal region of domain I (23). Systemic transport of 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] and other dihydroxylated metabolites to target organs is managed by Gc-globulin. The dihydroxylated metabolites, particularly 1,25[(OH).sub.2][D.sub.3], bind to a nuclear receptor at the target cells, followed by subsequent generation of appropriate biological responses. Plasma clearance of Gc-globulin does not appear to be altered by 25-hydroxyvitamin [D.sub.3] [25(OH)[D.sub.3]] occupancy. The binding affinities of Gc-globulin for vitamin D metabolites differ, providing differential availability of "free" (protein-unbound) steroids. For 1,25[(OH).sub.2][D.sub.3], which binds with lower affinity than 25(OH)[D.sub.3], the fraction that exists as the free steroid is 0.4% of the total concentration, compared with 0.04% of total for 25(OH)[D.sub.3]. Other tasks of Gc-globulin, such as actin binding, alter neither its binding capacity nor its affinity for vitamin D steroids.
Gc-globulin also transports endotoxin. A clinical role of this binding activity has been suggested in patients with peritonitis because Gc-globulin concentrations could predict organ failure in this condition (24). Thus, Gc-globulin could be an important scavenger of endotoxin in situations of endotoxinemia, such as septic conditions.
RESPONSE IN TISSUE INJURY OR INFECTION
There are 3 major Gc-globulin responses in tissue injury (25): One response is in the actin-scavenging system, working in concert with gelsolin, as described above. Another response involves the release by activated T and B cells of enzymes that process O-linked carbohydrate side chains of Gc-globulin, transforming the molecule into Gc-MAF. In turn, Gc-MAF stimulates macrophage activity at the tissue site. The immune response is controlled by Gc-MAF, inducing apoptosis in activated macrophages via caspase induction. The third response of Gc-globulin to tissue injury is to bind to circulating neutrophils, which stimulates chemotactic localization to specific tissue sites. Additional functions include the inhibition of actin-induced platelet aggregation (26) and the stimulation of osteoclast activity and bone resorption by Gc-MAF (27). All of these findings strongly suggest that Gc-globulin exerts more complex physiologic functions than clearance of actin released by necrotic cells and tissues from the circulation.
[FIGURE 2 OMITTED]
GC-GLOBULIN AND CHEMOTACTIC ACTIVITY OF COMPLEMENT FACTOR 5-DERIVED PEPTIDES
Gc-globulin exerts immunomodulatory functions through enhancing complement factor 5 (C5)-mediated signaling. Enhancement of C5a-dependent chemotactic activity by Gc-globulin has been observed in several cell types, primarily monocytes and neutrophils (28). C5a elicits multiple effects on target cells, i.e., chemotaxis, primarily interacting with the cell-associated form of Gc-globulin present on the plasma membrane of diverse cell types (1).
Because Gc-globulin is found in high concentrations in plasma as well as several other body fluids, including breast milk, seminal fluid, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid of patients with chronic obstructive pulmonary disease, this interaction is patho-physiologically relevant, indicating that Gc-globulin enhances the recruitment of immunocompetent cells to inflammatory foci via activation of C5a-mediated signaling (29). Additional evidence for Gc-globulin as a major serum factor for chemotactic enhancement is provided by experiments demonstrating that Gc-globulin-depleted serum lacks chemotactic enhancing activity for C5a.
Both the binding of Gc-globulin to C5a and the generation of C5a cochemotactic activity show a slightly delayed response to inflammation (maximum activity is observed at <45 min) (30), which is most likely attributable to the expression of proteases that modify the Gc-binding site or Gc-globulin itself. A direct interaction of Gc-globulin with the C5a receptor as explanation for its cochemotactic effect was excluded by experiments showing that Gc-globulin does not alter the affinity of C5a for the C5a receptor (29). After maximum activity is reached, degradation of Gc-globulin by activated neutrophils is observed only after 2 to 3 h, indicating that prolonged binding of Gc-globulin is a prerequisite for the generation of cochemotactic activity. Other studies showed that neutrophil elastase and thrombospondin-1 might effectively control the binding of Gc-globulin to neutrophils (31).
Zhang and Kew (32) localized a C5a/C5adesArgbinding region in the Gc-globulin protein between amino acid residues 126 and 175. This common sequence and chemotactic activity are identical among the 3 major isoforms of Gc-globulin (Gc-1F, Gc-1S, and Gc-2). Circulating Gc-globulin colocalizes with both CD44 and annexin A2 receptors on the cell surface and may use both pathways to enhance C5a-mediated chemotaxis (33). Annexin A2 and CD44 are receptors involved in cell movement (34, 35). The annexin A2 receptor also associates with the cell-surface vitamin D [1,25[(OH).sub.2][D.sub.3]] receptor in lipid rafts (36, 37), and it has been hypothesized that the interaction is essential for the endocytotic uptake of vitamin D. CD44 and annexin A2 receptors are widely expressed on the surface of many cell types, including most leukocytes, and thus are targets for Gc-globulin to mediate its systemic effects (34, 35). This enables Gc-globulin to function any time C5a is generated.
Immunoassay Methods for Gc-Globulin Measurement
The concentration of Gc-globulin can be determined as total Gc-globulin (actin-free and actin-complexed Gc-globulin) and as actin-free Gc-globulin.
Serum concentrations of total Gc-globulin range from ~200 to 600 mg/L in healthy donors. The concentration of total Gc-globulin is measured by simple immunoassay techniques with polyclonal or monoclonal antibodies (Table 1). However, the choice of method depends on the apparatus, reagents, and experience of the laboratory concerned.
Gelsolin is measured by nephelometry (range, 151-621 mg/L in healthy donors) (9). The determination of actin-free Gc-globulin is more complex. Most published methods make use of rocket immunoelectrophoresis (38) and polyacrylamide gel electrophoresis (without sodium dodecyl sulfate) and semiquantification by immunoblotting (39) (Table 1). These are time-consuming, indirect, and relatively imprecise procedures, taking more than 1 working day to obtain results.
A direct way of measuring actin-free Gc-globulin is by a rapid sandwich ELISA (Dianova). Actin-free Gc-globulin bound to the coat of a monoclonal antibody that is capable of binding Gc-globulin, free or complexed with actin, is detected with a second labeled monoclonal antibody that specifically binds to epitopes of the actin-free Gc-globulin. Thus, only actin-free Gc-globulin is measured, with an assay time of <1 h. The selective detection of actin-free Gc-globulin in human serum makes it possible to trace the free Gc-globulin reserve in critically ill patients in a short turnaround time during their clinical course. The reference values for actin-free Gc-globulin depend on the methods used (Table 1). Serum concentrations of actin-free Gc-globulin determined by the sandwich ELISA range from ~92 to 332 mg/L in healthy donors. The 2.5th centile value for actin-free Gc-globulin in healthy persons, as determined by the rapid sandwich ELISA, is ~100 mg/L. Values <100 mg/L should be regarded as potentially indicative of a reduced reserve of actin-free Gc-globulin.
Clinical Relevance of Gc-Globulin
Various studies have demonstrated a direct correlation between serum concentrations of Gc-globulin and the survival rate of polytraumatized patients, showing that the Gc-globulin concentration is decreased shortly after trauma, largely because of its increased consumption within the actin-scavenging system. Measurement of the Gc-globulin concentration after trauma can be used for early identification of patients with increased risk of lethality. Additional studies revealed that, in polytraumatized patients, concentrations of total and actin-free Gcglobulin are significantly higher in survivors than in nonsurvivors (15,17, 40).
ACUTE LIVER FAILURE
Deficiency of Gc-globulin plays an important role in the pathophysiology of liver injury in both non-acetaminophen-induced acute hepatic failure (non-AHF) and AHF. The admission concentrations of serum Gc-globulin provide prognostic information that is precise enough to assess the course of the disease, with a reliability that is comparable to the Kings College criteria (14). Because Gc-globulin is synthesized in the liver, hepatic insufficiency decreases serum concentrations of Gc-globulin, further aggravating the situation through impairment of the actin-scavenging system. Admission serum concentrations of total Gc-globulin were decreased by 75% in patients with AHF, and patients who had the most fulminant course had the lowest concentrations (41, 42). The number of organ failures inversely correlated with serum concentrations of Gc-globulin (13).
Several independent clinical studies (16,43) have shown that low Gc-globulin concentrations are associated with a poor prognosis for survival and an increased risk of developing MODS in sepsis. This association is similar to that of traditional clinical risk factors, such as the number and kind of traumatized organs. Early decreases in circulating actin-free Gc-globulin were associated with the development of disseminated intravascular coagulation, whereas persistently low concentrations were correlated with the occurrence of ARDS (16). The identification of Gc-globulin as an endotoxin-binding protein suggests its involvement in the clearance of this important septic mediator. Impairment of this function by decreases in the systemic concentration of Gc-globulin might promote the development of septicemia and, hence, could be deleterious for the patient.
Gc-globulin has an array of biological activities and therefore a range of potential therapeutic applications (25). Measurement of total Gc-globulin, and particularly of actin-free Gc-globulin, could aid in the management of patients with severe injury, so that decisions can be made whether to treat with plasma (a source of Gc-globulin) or Gc-globulin concentrate, if available. The knowledge of Gc-globulin concentrations can also contribute to decision-making for acute liver transplantation.
The macrophage-stimulating activities of Gc-globulin have led to applications, including inhibition of the growth of various types of cancer. Chronic obstructive pulmonary disease (COPD) is thought to have a genetic link, possibly involving the gene encoding Gc-globulin (44). The authors concluded that the damage to the lung parenchyma might be related to the ability of Gc-globulin to be converted to Gc-MAF, which in turn increases macrophage stimulation. The presence of a homozygous Gc2 allele provided protection against the deleterious effects of chronic cigarette smoking (44). This observation raises the possibility that a recombinant product based on Gc2 could serve as a means of ameliorating COPD.
It has been suggested that, in patients with advanced cancer, macrophages cannot be activated because cancer cells efficiently inactivate Gc-globulin. The cancer cells release an endoglycosidase (N-acetylgalactosaminidase) that inactivates Gc-MAF. Replacing Gc-MAF could restore the capability of macrophages to remove cancer cells (45) and could reverse the immunosuppression. The inactivation of Gc-MAF by a-N-acetylgalactosaminidase is also thought to be involved in the etiology of immune-suppressed conditions, such as HIV infection and systemic lupus erythematosus (46). Treatment of these patients with Gc-MAF to stimulate macrophages could offer a means of clearing immune complexes. These data provide evidence that Gc-MAF might have a spectrum of activities relevant for the treatment of cancer by improving immune surveillance.
Evaluations of the modulation of Gc-globulin concentrations under specific disease conditions could be included in future therapeutic trials and may further support the relevance of this intriguing protein in clinical medicine from both the diagnostic and therapeutic points of view.
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URSULA MEIER,  * OLAV GRESSNER,  FRANK LAMMERT  and AXEL M. GRESSNER 
 Institute of Clinical Chemistry and Pathobiochemistry and Central Laboratory, Rheinisch-Westfalische Technische Hochschule (RWTH)-University Hospital Aachen, Aachen, Germany.
 Department of Internal Medicine I, University of Bonn-University Hospital Bonn, Bonn, Germany.
 Nonstandard abbreviations: Gc, group-specific component; MAF, macrophage (and osteoclast)-activating factor; MODS, multiple organ dysfunction syndrome; ARDS, acute respiratory distress syndrome; 1,25[(OH).sub.2][D.sub.3], 1,25-dihydroxyvitamin [D.sub.3] (calcitriol); 25(OH)[D.sub.3], 25-hydroxyvitamin [D.sub.3] (calcidiol); AHF, acetaminophen-induced acute hepatic failure; and COPD, chronic obstructive pulmonary disease.
* Address correspondence to this author at: Institute of Clinical Chemistry and Pathobiochemistry and Central Laboratory, Rheinisch-Westfalische Technische Hochschule (RWTH)-University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. Fax 49-241-8082512; e-mail email@example.com.
Received December 21, 2005; accepted May 2, 2006.
Previously published online at DOI: 10.1373/clinchem.2005.065680
Table 1. Analysis of circulating Gc-globulin in disease conditions. (a) Total Gc-globulin Disease Concentration Healthy persons 200-600 mg/L Fulminant hepatic [less than or equal to] 100 mg/L failure AHF (d) [less than or equal to] 120 mg/L Multiple trauma [less than or equal to] 200 mg/L Total Gc-globulin Disease Method(s) Reference Healthy persons Immunodiffusion, immunoturbidimetry, (40) immunonephelometry, inhibition- ELISA Fulminant hepatic Rocket immunoelectrophoresis (17) failure AHF (d) Rocket immunoelectrophoresis (15) Multiple trauma Rocket immunoelectrophoresis (14) Actin-free Gc-globulin Disease Concentration Healthy persons 92-332 mg/L Fulminant hepatic [less than or equal to] 34 mg/L failure AHF (d) Multiple trauma Actin-free Gc-globulin Disease Method Reference Healthy persons Sandwich ELISA (b) Fulminant hepatic PAGE (c) without SDS, (39) failure quantified by immunoblotting AHF (d) Multiple trauma (a) Compiled from Refs. (14, 15, 17, 39, 40). (b) Determined by manufacturer. (c) PAGE, polyacrylamide gel electrophoresis; SDS, sodium dodecyl sulfate. (d) Acetaminophen-induced.
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|Author:||Meier, Ursula; Gressner, Olav; Lammert, Frank; Gressner, Axel M.|
|Article Type:||Clinical report|
|Date:||Jul 1, 2006|
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