C1q and tumor necrosis factor superfamily: modularity and ... - Cell Press

Review

TRENDS in Immunology

Vol.25 No.10 October 2004

C1q and tumor necrosis factor superfamily: modularity and versatility Uday Kishore1,2, Christine Gaboriaud3, Patrick Waters1, Annette K. Shrive4, Trevor J. Greenhough4, Kenneth B.M. Reid5, Robert B. Sim5 and Gerard J. Arlaud3 1

Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK, OX3 9DS Institute for Medical Microbiology, Justus-Liebig-University, Frankfurter Strasse 107, D-35392 Giessen, Germany 3 Laboratoire de Cristallographie et Cristallogenese des Proteines and Laboratoire d’Enzymologie Moleculaire, Institut de Biologie Structurale Jean Pierre Ebel, CEA-CNRS-Universite Joseph Fourier, 41, rue Jules Horowitz, 38027 Grenoble Cedex 1, France 4 School of Life Sciences, Keele University, Staffordshire, UK, ST5 5BG 5 Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK, OX1 3QU 2

C1q is the target recognition protein of the classical complement pathway and a major connecting link between innate and acquired immunity. As a charge pattern recognition molecule of innate immunity, C1q can engage a broad range of ligands via its globular (gC1q) domain and modulate immune cells, probably via its collagen region. The gC1q signature domain, also found in many non-complement proteins, has a compact jelly-roll b-sandwich fold similar to that of the multifunctional tumor necrosis factor (TNF) ligand family. The members of this newly designated ‘C1q and TNF superfamily’ are involved in processes as diverse as host defense, inflammation, apoptosis, autoimmunity, cell differentiation, organogenesis, hibernation and insulinresistant obesity. This review is an attempt to draw structural and functional parallels between the members of the C1q and TNF superfamily. C1q is the key subcomponent of the classical pathway of complement activation and a major connecting link between classical pathway-driven innate immunity and IgG- or IgM-mediated acquired immunity [1]. Binding of C1q to IgG- or IgM-containing immune complexes via the ligand-recognition gC1q domain induces a conformational change in the collagen region (Figure 1), leading to the autoactivation of C1r, which, in turn, activates C1s. C1r and C1s, the two serine protease proenzymes, together with C1q constitute C1, the first component of the classical complement pathway [2]. The activation of the C1 complex subsequently leads to the activation of the C2–C9 components of the classical pathway and formation of the terminal membrane attack complex. In addition to being the key component of the classical complement pathway, which is aimed at antimicrobial defense, C1q is involved in several other immunological processes (Table 1), including maintenance of immune tolerance via clearance of apoptotic cells, phagocytosis of bacteria, neutralization of retroviruses, cell adhesion, and Corresponding authors: Uday Kishore ([email protected]; [email protected]). Available online 20 August 2004

modulation of dendritic cells (DCs), B cells and fibroblasts [1,3]. Its ability to carry out such diverse functions is aided by its capacity to engage a broad range of ligands, such as envelope proteins of certain retroviruses, b-amyloid fibrils, lipopolysaccharides (LPS), porins from Gram-negative bacteria, phospholipids (PL), apoptotic cells and some acute phase reactants, including pentraxins (Table 1) [1,3]. The majority of C1q ligands are recognized via the heterotrimeric gC1q, which is an extremely efficient and versatile charge pattern recognition domain. The gC1q signature domain is also found in a variety of non-complement proteins, including collagen VIII and X, precerebellin, hibernation proteins, multimerin, adiponectin, saccular collagen and elastin microfibril interface-located protein (EMILIN) [3,4] (Table 2). A major advance in the understanding of the gC1q structure–function relationship came with the elucidation of the crystal structure of the homotrimeric gC1q domain of mouse ACRP30 [5]. It revealed a structural and evolutionary link between tumor necrosis factor (TNF) and gC1q-containing proteins, and hence recognition of a C1q and TNF superfamily. Studies involving transgenic and genetically deficient mice, together with gene mutations found in patients, have suggested aspects of immunity and energy homeostasis where members of C1q and TNF superfamily cross over. Here, we discuss the overall structural and functional aspects of the C1q and TNF superfamily proteins, and speculate on how modularity within the gC1q domain has been exploited to achieve functional versatility by the superfamily members.

Modular organization of the gC1q domain The gC1q domain of C1q is composed of the C-terminal regions of its A (ghA), B (ghB) and C (ghC) chains [4] (Figure 1). Given the heterotrimeric organization of the gC1q, it has been debated whether modules ghA, ghB and ghC have distinct ligand-binding properties, or that the ability of C1q to bind its ligands is dependent upon a

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552

(a)

N-term 3-9 aa


CLR ~81 aa


gC1q ~135 aa

Unit

(b)

223 aa

A

A–chain

226 aa

B

B–chain

217 aa

C

C–chain

A

C C

A–B dimer B (e)

C

C C

C–C dimer C 5 nm

(c)

11.5 nm 7 nm Structural unit A–B C–C B–A

(d)

11.2 nm


Figure 1. Structural organization of the C1q molecule. C1q (460 kDa) is composed of 18 polypeptide chains (6A, 6B and 6C). (a) The A, B and C chains each have a short N-terminal region (containing a half-cystine residue involved in interchain disulfide bond formation), followed by a collagen region (CLR) of w81 residues and a C-terminal globular region (gC1q domain) of w135 residues. (b) The interchain disulfide bonding yields 6A–B dimer subunits and 3C-C dimer subunits. The triple-helical collagen region in the A and B chains of an A–B subunit, together with one of the C-chains present in a C–C subunit, form a structural unit (ABC–CBA), which is held together by both covalent and non-covalent bonds (c). Three of these structural units associate, via strong non-covalent bonds in the fibril-like central portion, to yield the hexameric C1q molecule that has a tulip-like structure, as also found in mannose-binding protein, surfactant protein A and ficolins [77] (d). The crystal structure of the gC1q domain of human C1q (Protein Data Bank code 1PK6, depicted as a ribbon diagram of ghA in blue, ghB in green, ghC in red, with the calcium ion shown as a yellow ball), has revealed a compact, spherical, ˚ diameter), held together predominantly by non-polar interactions, with non-crystallographic pseudo-threefold symmetry (e). The three gC1q heterotrimeric assembly (50 A modules show clear differences in their electrostatic surface potentials, which in part explains modularity in terms of ligand recognition [11].

combined, globular structure [6,7]. Studies using recombinant forms of ghA, ghB and ghC have suggested that each of the three modules of gC1q can bind its preferred ligand independently [7]. ghA can bind heat-aggregated IgG and IgM, in addition to HIV-1 gp41-derived loop peptide; ghB prefers aggregated IgG to IgM, in addition to b-amyloid peptide (bA1–42); whereas ghC shows preference for IgM as well as HTLV-I gp21 peptide. Both ghA and ghB can inhibit C1q-dependent hemolysis of IgG- and IgM-sensitized sheep erythrocytes, ghC being a better inhibitor than ghB in the case of IgM-coated erythrocytes [7–10]. The crystal structure of the native gC1q has supported the general view of the modular nature of the heterotrimer [11] (Figure 1e). Whereas ghA and ghC both show a combination of basic and acidic residues scattered on their external face, ghB shows a predominance of positive charges, especially a continuous patch of Arg101, Arg114 and Arg129, involved in the C1q–IgG interaction [12]. Thus, the modular organization of the heterotrimeric assembly, together with the different surface charge pattern and spatial orientation of individual modules, www.sciencedirect.com

confers flexibility and versatility to the ligand recognition of gC1q [6,11]. Structural modeling has suggested a predominant role for the ghB module in the C1q–IgG interaction [7,8,10,11]. As the most accessible of the three modules within the gC1q domain, ghB seems best located for binding IgG. The most attractive model attempting to describe the ghB–IgG interaction positions the two molecules in such a way that Asp270 and Lys322 of IgG form salt bridges with Arg129 and Glu162 of ghB, respectively, with Arg114 providing an additional ionic interaction. In this orientation, Arg129 appears to ‘act as a wedge’ between the CH2 and light chain constant domains. Therefore, the Fab/Fc orientation might be a crucial factor in dictating access of the ghB module to the CH2 domain. A recent mutational study has also suggested a dominant role for Arg114 of ghB and a subsidiary role for Arg129, Arg163 and His117 of ghB in the C1q–IgG interaction [12]. The flexibility and diversity of C1q binding is further highlighted by the interaction of gC1q with C-reactive protein (CRP), a major acute phase reactant that binds,

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Table 1. Interactions between gC1qa and its ligands Ligands IgG

IgM

CRP

SAP and PTX3

Decorin

Outer membrane proteins from Gram-negative bacteria, lipopolysaccharide (LPS), lipid A Viral proteins, e.g. gp41 of HIV-1, gp21 of HTLV-I, p15e of MuLV

b-amyloid and familial dementia peptides Apoptotic cells

Phospholipids (PLs) a

Interacting sites/motifs Glu318, Lys320, and Lys322 in mouse IgG2b, which is highly conserved in different IgG isotypes. In human IgG1 Asp270, Lys322, Pro329, Pro331 and residues Lys326 and Glu333 are implicated. Hexameric and pentameric IgM in the ‘staple’ form (bound to antigen) bind gC1q via the Cm3 domain involving His, Asp/Glu and Pro residues at 430–434. The gC1q binds to the central ‘pore’ in the planar pentamer of CRP when CRP has bound to a target such as chromatin or bacterial C-polysaccharide: one C1q head binds per pentameric CRP through one of the five available binding sites on CRP. A central role for a series of residues including CRP Tyr175, Glu88 and Asp112, and Lys114 from a neighboring protomer has been described. Because SAP is a homolog of CRP, its binding might be similar. However, CRP Asp112 is not conserved in SAP or PTX3. PTX3 binds via gC1q. Decorin might bind to the ‘neck’ region of C1q (between gC1q and collagen domain), or to both domains via decorin core protein. C1q binds directly to the surfaces of many Gram negative bacteria without the need for antibody. The gC1q binding is mediated by lipid A, LPS and porins. OmpK36 (from Klebsiella pneumoniae) competes directly with IgG for binding to C1q. Binding to lipid A and LPS is mainly via the phosphate groups of lipid A. C1q binds directly to many viruses, enveloped and non-enveloped. The ghA binds residues 601–613 (loop region) within the envelope protein gp41 of HIV-1 (especially Lys608, Leu609 and Ile610). The Ala substitution of all hydrophobic residues (including the four-carbon aliphatic moiety of the Lys608 side chain) within the loop abolishes the C1q–gp41 interaction. C1q also binds the HTLV-I gp21 peptide 400–429, which is required for syncytium formation. C1q globular heads bind to the acidic N-terminal 1–11 region of Alzheimer b-amyloid peptide and to the N-terminal regions of familial dementia peptides. C1q binds apoptotic cells directly and via pentraxins. The sites of interaction might include anionic PLs and surface proteins. Surface blebs of apoptotic keratinocytes and peripheral blood mononuclear cells, which contain autoantigens are targeted in SLE.

C1q binds cardiolipin and other anionic PLs.

Implications/comments C1q also interacts with the Fab (light chain constant domain), supporting observations that Fab/Fc flexibility has a crucial role in C1q binding.

Refs [11,45,46]

Monomeric IgM, fixed to antigen, does not bind C1q. Hexameric IgM generally activates the classical pathway better than pentameric IgM, possibly reflecting better symmetry for binding one entire C1q molecule. Modeling studies suggest a complementarity of shape between the top of gC1q and the central pore of the pentameric CRP ring, which involve ghA, ghB and CRP Tyr175 and Asp112. CRP binds chromatin and might have a major role in clearing chromosomal material from necrotic cells, via C1q binding.

[47]

Immobilized SAP binds C1q but there is controversy as to whether this results in complement activation. PTX3 mediates complement activation on apoptotic cells. Modulation of the classical pathway activation in the tissue.

[48,49]

[3,11–15]

[50]

Many pathogenic Gram-negative bacteria evade C1q fixation by steric hindrance of C1q binding.

[51,52]

C1q binding to viruses might result in virus neutralization. C1q–gp41 interaction leads to enhanced infection of complement-receptor-bearing cells, instead of viral lysis. Interaction between HTLV-I peptide and gC1q might affect the fusion process required for syncytium formation.

[3,7]

Classical pathway activation leads to inflammation in neuritic plaques.

[53–55]

C1q deficiency can cause SLE as a result of an impaired clearance of apoptotic cells. In C1q knockout mice, which have glomerulonephritis with immune deposits, a large number of apoptotic bodies are also present in diseased glomeruli. C1q might protect against autoimmunity by serving as an opsonin in the efficient recognition and physiological clearance of apoptotic cells, hence be required to maintain immune tolerance. Possible role in clearance of apoptotic and necrotic cells.

[7,24]

[52]

Abbreviation: CRP, C-reactive protein; gC1q, globular domain of C1q; PL, phospholipid; PTX3, pentraxin 3; SAP, serum amyloid protein; SLE, systemic lupus erythematosus.

via the face of its pentameric ring, to the phosphocholine component of membrane PL [13,14]. The overall dimensions of C1q and CRP molecules appear to suggest that only one gC1q can bind to each CRP pentamer through one of the five available binding sites on CRP. This interaction involves a series of residues, including CRP Tyr175, Glu88 and Asp112, and Lys114 from a neighboring subunit [15]. Molecular modeling has revealed a shape complementarity between the top of the gC1q and the central pore of the pentameric CRP ring, suggesting a central role for ghA, ghB and CRP Asp112 and Tyr175 in this interaction [11]. However, given severe steric restraint between the two structures, it is apparent that structural changes in CRP, rather than participation of bound ligand, is required for www.sciencedirect.com

this interaction [3]. It is evident that the compact heterotrimeric structure of the gC1q domain clearly facilitates ligand recognition by two or even three subunits, thus providing a structural basis for the extremely versatile recognition properties of C1q [11]. A novel C1q family A variety of collagenous and non-collagenous noncomplement proteins also contain a gC1q signature domain (w140 residues long) and thus constitute a novel C1q family [1] (Table 2; Figures 2–4). Except in precerebellin and multimerin, the gC1q domain is always located at the C-terminus of a collagen-like sequence. Comparative sequence analysis between gC1q domains of

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Table 2. Proteins with a gC1qa domain, their cell sources and functions Protein ACRP30 (adiponectin)

Tissues of origin and presentation Serum protein produced by adipocytes: 5–10 mg/ml in normal plasma.

C1q

Serum protein produced by the liver: 70 mg/ml.

EMILIN-1

Connective tissue, blood vessels, skin, heart, lung, kidney, cornea, small intestine, aorta, uterus and appendix; fetal heart and lungs. Fetal heart and adult lung; intermediate levels in peripheral leukocytes, placenta and spinal cord; major component of the cochlear basilar membrane in the mouse. Blood vessel endothelial cell surface including capillaries, veins, arterioles and muscular arteries. Platelet a-granules, endothelial cell Weibel–Palade bodies, megakaryocytes, platelets, endothelium and subendothelium of blood vessels; placenta, lung and liver. Plasma protein produced by the liver.

EMILIN-2

EMILIN-3 (multimerin 2) EMILIN-4 (multimerin 1)

HP-20, -25, -27

Precerebellin

Saccular collagen Collagen VIII

Collagen X

Expressed in the cerebellum associated with postsynaptic structures of the Purkinje cell membrane and the dorsal cochlear nucleus; brain. Produced by specialized secretory-supporting cells at the outer perimeter of the saccular macula; also found in saccular otolithic membrane. Produced by endothelial cells; major constituent of Descemet’s membrane (specialized basement membrane of corneal endothelial cells); optic nerve, aorta, umbilical cord and tissues undergoing remodeling; calvarium, eye and skin. Produced by hypertrophic chondrocytes in the epiphyseal growth plate of long bones, ribs and vertebrae during endochondral bone formation, bone fracture callus and osteoarthritic cartilage.

CORS26

Prechondrocytes in developing cartilage; colon, small intestine, placenta, fibroblasts, white adipose tissue, blood and kidney; osteosarcoma, chondroblastoma and giant cell tumors.

CTRP5

Retinal epithelium, lung, placenta, cerebrum and liver.

Function An antidiabetic and antiatherogenic adipokine; insulin sensitivity, energy homeostasis, and lipid and carbohydrate catabolism; reduced blood levels in obesity, insulin resistance and type 2 diabetes; resolution of inflammation. See Table 1 and Figure 1. Smooth muscle adhesion to elastic fibers, elastogenesis and regulation of vessel assembly.

Refs. [30,33–35,56]

See references in Table 1 [57]

Development of heart chambers and cochlear basilar membrane, and the compositional and functional heterogeneity of the extracellular matrix.

[58]

Proposed role in vasculogenesis, angiogenesis or hemostasis and cell-matrix adhesion. As a factor V/Va binding protein, it might play a role in platelet factor V storage and stability; adhesion functions via an RGDS motif once released extracellularly. HP-20, -25 and –27 form a 140 kD complex with a HP-55 serpin; this complex disappears from the blood during hibernation. Potential role in the development and stability of the Purkinje cell synapse.

[59]

Structural constituent of the otolithic membrane, a sensory accessory membrane in the inner ear involved in vestibular function. Vascular tissue development and remodeling, cell migration, plaque stability and thrombus organization.

[38,64]

Secreted into the extracellular matrix of presumptive ossification zones of cartilage; formation of a hexagonal lattice and interaction with proteoglycans; eventually replaced by bone extracellular matrix. Embryonic skeletal development; might act as a growth factor, or be involved in signaling via three possible phosphorylation sites; implicated in bone tumor; a potential candidate gene in the development of arthritis. Formation of an extracellular hexagonal lattice between RPE and Bruch’s membrane in the retinal epithelium.

[16,68,69]

[60]

[37,61]

[62,63]

[65–67]

[70,71]

[39]

a Abbreviations: ACRP30, adipocyte complement-related protein – 30 kD; CORS26, collagenous repeat containing sequence of 26 kDa protein; CTRP5, C1q and tumor necrosis factor related protein 5; EMLIN-1, Elastin microfibril interface-located protein 1; gC1q, globular domain of C1q; HP, hibernation protein of Siberian chipmunk; RGDS, Arg-GlyAsp-Ser; RPE, retinal pigment epithelium.

C1q family members shows that whereas limited variability occurs at several positions, only five residues are strictly conserved throughout the C1q family (Figure 3). Four structures of gC1q domains, namely those of mouse ACRP30 [5], human collagen X [16], mouse collagen VIII (a1) [17] and human C1q [11], have been solved ˚ . Each by X-ray crystallography, at resolutions of 1.9–2.1 A gC1q domain exhibits a ten-stranded b-sandwich fold with a jelly-roll topology, consisting of two five-stranded b- sheets (A 0 , A, H, C, F) and (B 0 , B, G, D, E), each made of antiparallel strands (Figure 4a–c). Each of the five conserved residues within C1q family proteins belongs to the hydrophobic core of the gC1q domain. The b-strands are strongly conserved in the different gC1q domains, both with respect to their relative orientation and size (Figure 3, 4a–c). By contrast, the loops connecting the www.sciencedirect.com

b-strands exhibit significant variability, as is the case in the extended segments A-A 0 and G-H, which exhibit markedly different sequences and structures in the ghA, ghB and ghC modules (Figures 3,4a). All structures reveal similar tight assemblies with pseudo-threefold symmetry, resulting in globular, almost ˚ in diameter). The N- and spherical domains (45–55 A C-termini of the three subunits emerge on the same side of the trimer and are adjacent to one another (Figure 4d). In the case of C1q (Figure 4e), the subunits are arranged clockwise in the order ghA (blue), ghB (green) and ghC (red) when viewed from the top. Structural homology is very high between collagen VIII and X, with a root ˚ , but is much mean square deviation (rmsd) of only 0.61 A lower between distantly related collagen VIII and ˚ ). Trimerization involves a very ACRP30 (rmsdZ2.3 A

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Motifs NH2

Hibernation protein gC1q domain Collagen like region

Precerebellin

NH2

EGF NH2

Leucine zipper

CORS-26

Coiled-coil NH2

Partial EGF

C1q

RGDS domain NH2

Possible glycosylation sites

ACRP-30/Adiponectin

Cysteine residues NH2

Saccular collagen

NH2

Type X collagen

NH2

Type VIII collagen - 1

NH2

EMILIN - 1

Multimerin

NH2

0

100

200

300

400

500

600

700

Residue number

800

900

1000

1100

1200

1300


Figure 2. Cartoon depicting the structural motifs of the C1q family members. Proteins belonging to the C1q family have a C-terminal gC1q signature domain [1,4,6]. Most members of the C1q family have a triple-helical Gly-X-Y collagen repeat, with the exception of precerebellin, and multimerin. The gC1q are either homotrimeric (type VIII and X collagen, multimerin, ACRP30 and saccular collagen) or heterotrimeric (C1q and hibernation proteins, and probably precerebellin) structures. Although collagen VIII is considered to be composed of two distinct gene products (a1 and a2), both chains can also preferentially form pepsin-resistant homotrimers and exist as two distinct proteins [67]. Elastin microfibril interface-located protein (EMILIN) has a region containing two leucine zippers and at least four heptad repeats, with a high potential for forming amphipathic coiled-coil a-helices, and at the N-terminus, a partial epidermal growth factor (EGF)-like motif, as found in multimerin [57,58]. Multimerin also has an RGDS (Arg-Gly-Asp-Ser) motif, EGF domain and a domain containing coiled-coil structures. Multimerin and EMILIN are unique in having a-helical coiled-coil structures, which might be involved in trimerization or higher-order multimerization.

tight association of the subunits, although with significant variations, as judged from total buried surface, which are ˚ 2) and C1q (5490 A ˚ 2) than much lower in ACRP30 (5324 A 2 2 ˚ ˚ in collagen VIII (6150 A ) and X (7360 A ), accounting for the exceptional stability of the collagen VIII and X molecules [16]. Trimerization also involves a central interface and lateral contacts which are hydrophobic near the base, becoming progressively more polar towards the top. These interactions involve residues contributed by the b-sheet formed by strands A 0 , A, H, C and F, with a major contribution from strands C and F (Figure 4e). This results in the creation of a central solvent-filled channel, which is discontinuous in C1q and whose access is blocked at both ends. Irrespective of whether the structures are homotrimeric (ACRP30 and collagen VIII and X) or heterotrimeric (C1q), all trimers assemble in a similar way. However, tentative assembly of C1q homotrimers in silico has been shown to result in severe steric www.sciencedirect.com

hindrances, providing a structural basis for their assembly only as heterotrimers [11]. Near the top of the solvent channel, the collagen X structure has a buried cluster of three Ca2C ions surrounding the one located on the threefold symmetry axis of the trimer (Figure 4f). It is coordinated by acidic residues and other residues (Figure 3), which together form an intricate network of ionic bonds which probably contribute to the high stability of the collagen X gC1q trimer [16]. This cluster is absent from the collagen VIII structure, due to the presence of Lys692 in place of Thr629 in its solvent channel [17]. This enables the amino groups to substitute for the peripheral Ca2C ions while maintaining a similar network of interactions near the apex of the trimer. Whereas loops A-A 0 , G-H and E-F are partly disordered in the Ca2C-free form of ACRP30 [5], they are structured in the Ca2C-bound form (Figure 4b), providing support for a stabilizing effect of Ca2C. A single Ca2C ion,

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Figure 3. Sequence alignment of the gC1q domains of human collagen X (Col_X), mouse collagen VIII (Col_VIII), mouse ACRP30, human C1q, human C1q-related factor (C1q_RF), chipmunk hibernation proteins (HP_27, HP_25, HP_20), CORS26, human endoglyx-1/elastin microfibril interface-located protein (EMILIN)-3 (Endo_1), human precerebellin (Precer) and saccular collagen from bluegill sunfish (Saccol). Location of the b-strands is indicated on top of the sequences. Residues showing minimal variability are colored yellow and those strictly conserved in all known gC1q sequences are indicated underneath the alignment as a consensus sequence. Residues involved in intermodular interfaces are marked by #. Ca2C ligands are colored red, and those involved through their side chain are shown in bold. The free cysteine residue present in most gC1q domains is colored green, and Lys692 of collagen VIII is colored purple.

also located at the upper end of the central channel, is present in the C1q structure [11]. In contrast to the Ca2C cluster of collagen X, the Ca2C ion of C1q is well exposed to the solvent (Figure 4d), suggesting that, in addition to a stabilizing role, it might also participate in ligand recognition [11]. The surfaces of the collagen VIII and X structures have three strips, each containing eight aromatic residues partially exposed to the solvent, extending across the shallow grooves between the subunits [16,17]. In both cases, a detergent molecule is bound near the top of the grooves (Figure 4f), highlighting the hydrophobic nature of the strips, which probably initiate supramolecular assembly. Thus, the members of the C1q family exhibit subtle variations in the three-dimensional structure of the gC1q domain according to their functional requirements. As discussed below, the structural fold of the gC1q domain is homologous to the one described initially for TNF [18,19], suggesting an evolutionary link between the C1q and TNF families. The C1q and TNF superfamily The ACRP30 gC1q structure revealed a symmetrical trimer of b-sandwich subunits, each having a ten-strand www.sciencedirect.com

jelly-roll-folding topology, which is also present in the conserved C-terminal TNF homology domain (THD) within the TNF ligand family proteins [18,19]. Members of the TNF family are involved in a range of biological processes such as inflammation, adaptive immunity, apoptosis, energy homeostasis and tissue regeneration (Table 3). Each of the ten b-strands of ACRP30 can be superimposed with the ten strands of TNF-a, TNF-b and CD40L [5]. The relative positions and lengths of these b-strands are almost identical between ACRP30 and the TNF ligands [5]. The C1q and TNF family proteins also have similar gene structures: their gC1q or THD domains are each encoded within one exon, whereas introns in both families are restricted to respective N-terminal collagen or stalk regions, suggesting divergence from a common precursor molecule of the innate immune system, and thus establishing a C1q and TNF molecular superfamily [5]. This jelly-roll structure is remarkably similar to the capsid proteins of plant viruses and mammalian picornaviruses including foot-and-mouth and poliovirus [18,19]. The presence of oligomerizing jelly-roll motifs in viruses is interesting because capsid proteins and members of the C1q and TNF superfamily are unrelated

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(a)


(b)

557

(c)

C F H G

A′ A

E

D

B′ B

SH N C (d)

(e)

(f) B′ G

B

D E

H

A

A′

C

F

C

C N

C

N

N TRENDS in Immunology

Figure 4. Structural features of C-terminal globular region (gC1q) signature domains in the C1q family. (a) Superimposed structures of modules A, B and C of human C1q Protein Data Bank (PDB) code 1PK6. The modules are colored blue (ghA), green (ghB) and red (ghC). The free cysteine and the disulfide bond connecting b-strands D and E are shown in the case of module C. (b) Superimposed structures of the Ca2C-free (green) and Ca2C-bound (blue) forms of the mouse ACRP30 gC1q domain (PDB codes 1C28 and 1C3H). (c) Superimposed structures of the gC1q domains of mouse collagen VIII (pink) and human collagen X (blue) (PDB codes 1O91 and 1GR3). The side chain of Lys692 of collagen VIII is shown. (d) Side view and (e) top view of the gC1q domain of human C1q. Color coding is the same as in (a). N and C indicate the N- and C-terminal ends of each module. (f) Top view of the collagen X NC1 domain. The detergent molecules bound to the structure are shown in ball and stick format. Ca2C ions are represented as yellow balls.

and without any functional conservation. Given similar intracellular signaling domains of some TNF receptors and toll-like receptors (TLR), which function as germlineencoded receptors for surface proteins of pathogens, C1q and TNF proteins are likely to have descended via horizontal capture of a gene encoded by an ancient viral pathogen [5,20]. Functional overlaps between the members of the C1q and TNF families The TNF ligands are synthesized as type II membrane proteins which serve as cell contact-mediated regulators. They can be proteolytically cleaved as soluble homotrimers, with the exception of membrane-bound lymphotoxin (LT; which contains one LTa subunit and two subunits of LTb), B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) that can also form heterotrimers. The soluble forms can act as either agonists or antagonists of membrane-bound forms. TNF contributes towards inducing inflammation transiently and reversibly to foster immune cell networking (Table 3). www.sciencedirect.com

Some members induce apoptosis, others promote cell survival and some induce cell proliferation via activation of pathways involving nuclear factor-kB (NF-kB), C-Jun N-terminal kinase (JNK), p42 or p44 mitogen-activated protein kinase (MAPK) and p38 MAPK. The multiple functions assigned to TNF ligands have their genesis in the expression of TNF receptor (TNFR) by all cell types [20–22]. There are aspects of immune mechanisms and energy homeostasis in which members of the C1q and TNF superfamily cross over and effect similar or almost opposite pathophysiological outcomes [5,6]. TNF ligands have been implicated in the development of autoimmunity. Mice transgenically overexpressing BAFF secrete high levels of autoantibodies, such as rheumatoid factors and antinuclear antibodies, similar to the situation in systemic lupus erythematosus (SLE), and develop severe glomerulonephritis leading to kidney failure [23]. C1q deficiency is a likely cause of SLE, resulting from an impaired clearance of apoptotic cells. In C1q knockout mice, which have glomerulonephritis with immune deposits, a large

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Table 3. TNF ligands, their cell sources and functionsa TNF ligands LTa/bb

Cell source NK, T and B cells; DCs, macrophages

TNFa

Macrophages, NK, T and B cells, adipocytes

FasL (CD95L)

Activated splenocytes, thymocytes, eyes, testis

TRAIL

NK and T cells, DCs

TWEAK

Monocytes

CD27L CD30L CD40L

NK, T and B cells T cells and monocytes T and B cells

4-1BBL

B cells, DCs and macrophages T and B cells, DC, macrophages Macrophages, lymphoid cells, tumor cells T cells, DCs, monocytes, macrophages

OX40L APRIL BAFF

LIGHT

T cells, granulocytes, monocytes, DCs

VEGI

Endothelial cells

GITRL RANKL

DCs, macrophages, B cells Activated T cells and osteoblasts

EDA1,2

Skin

Functions Central to organogenesis of secondary lymphoid tissue; LTa ko mice are deficient in peripheral lymph nodes and Peyer’s patches; LTb ko mice are deficient in peripheral lymph nodes, Peyer’s patches, splenic germinal centers and FDCs. Multifunctional cytokine involved in inflammation, apoptosis and survival, cytotoxicity, production of IL-1 and IL-6, induction of insulin resistance; ko mice are susceptible to Listeria and resistant to LPS; deficient in splenic primary B cell follicle and organized FDC and germinal centers. Induction of cell-mediated cytotoxicity; death-inducing ligand (apoptotic suicide); involvement in angiogenesis and tumor progression; role in immune homeostasis; prevention of autoantibody production; ko mice have lymphadenopathy and systemic autoimmunity; immune complex glomerulonephritis. Induction of apoptosis selectively in tumor cells via death receptors; activation of NK cells, cytotoxic T cells and DCs; a potential tumor-specific cancer therapeutic; ko mice susceptible to tumor metastasis. Stimulation of cell growth and angiogenesis; induction of inflammatory cytokines; stimulation of apoptosis. Expansion and survival of T cells; T cell priming. Important for processes mediated by Th2 cells. Proliferation, differentiation, germinal center development, isotype switching, memory; ko mice do not develop germinal centers to thymus-dependent antigens, have impaired virus-specific CD4C T cell response, fail to develop memory cell response and have impaired T-cell-dependent macrophage activation. Expansion and survival of T cells; T-cell priming; ko mice have decreased CD8C T-cell expansion. Expansion and survival of T cells; T-cell priming; ko mice have DCs defective in costimulating Th cytokine production (impaired APC function). Role in T-cell-independent type II antigen response and T-cell survival; can induce proliferation and survival of non-lymphoid cells; role in lupus-like syndromes. Important survival and maturation factor for peripheral B cells; role in lupus-like syndromes; overexpression linked to autoimmune disease and B-cell neoplasia; ko mice have reduced IgG and IgM; blocked B-cell development and reduced mature circulating B cells, Initiator of T-cell costimulation signals causing CTL-mediated tumor and allograft rejection; a potential target for regulating cellular immunity; ko mice have reduced proliferative response of Vb8C CD8C to enterotoxin B. Potent inhibitor of endothelial cell proliferation (early G1 arrest) and inducer of apoptosis, angiogenesis and tumor growth. A regulator of regulatory T cells. Survival factor for activated DCs; maintenance of immune tolerance; also involved in osteoclast differentiation and activation, hence crucial for bone homeostasis; potential therapeutic target in osteoporosis, osteolytic metastatic cancer, arthritis and periodontitis; mammary gland lactation; ko mice have retarded growth after weaning, osteoporosis, deficient osteoclasts, defective tooth eruption and lack lymph nodes, but have normal spleen and Peyer’s patches. Hair follicle and sweat gland development; ko mice have no primary hair follicles or sweat glands and have malformed teeth; they also have hypoplastic hair, teeth and eccrine sweat glands.

a

Based on Refs [20–22,72–76]. Abbreviations: APC, antigen-presenting cell; APRIL, a proliferation-inducing ligand; BAFF, B-cell-activating factor; CTL, cytotoxic lymphocyte; DC, dendritic cell; EDA, ectodermal dysplasin; FDC, follicular dendritic cell; GITRL, glucocorticoid-induced TNFR family receptor ligand; IL, interleukin; ko, gene-deficient or gene knock-out; LIGHT, lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes; LPS, lipopolysaccharide; LT, lymphotoxin; RANKL, receptor activator of nuclear factor-kB ligand; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TRAIL, TNF-related apoptosis-inducing ligand; TWEAK, TNF-like weak inducer of apoptosis; VEGI, vascular endothelial cell growth inhibitor. b

number of apoptotic bodies are present in diseased glomeruli [24]. CD40L deficiency impairs CD4C T-cell priming, follicular dendritic cell (FDC) differentiation, germinal center formation and class switching. The IgM-expressing cells cannot undergo isotype conversion to IgG expression, leading to hyper-IgM syndrome [25]. C1q knockout mice also show significantly reduced production of T-cell-dependent antigen-specific IgG2a and IgG3 isotypes owing to reduced interferon-g production by T cells [26]. C1q therefore might be crucial to antigen delivery to FDCs and subsequent generation of a normal secondary antibody response. Furthermore, mutations in FasL are known in patients with autoimmune lymphoproliferative syndrome, which causes a lack of www.sciencedirect.com

apoptosis, massive lymphoid hyperplasia and autoantibody production [27]. C1q and TNF-a are known to be produced in response to infection as inducers of proinflammatory activators [28]. Curiously, C1q has also been shown to suppress LPS- and CpG-induced interleukin-12 p40 and TNF-a production in bone-marrow-derived DCs [29]. As a regulator of LPS and the TLR pathway, C1q inhibits the LPS-induced MyD88dependent pathway, leading to reduced NF-kB activity and delayed phosphorylation of MAPK [29]. Adiponectin can also suppress mature macrophage function by significantly inhibiting their phagocytic activity and their LPS-induced production of TNF-a, and thus might resolve inflammation [30]. C1q is also known to be

Review


antiproliferative (G1 mitotic arrest) and proapoptotic for human fibroblasts [31]. However, this effect of C1q, which involves p38 MAPK, is mediated by the collagen region and not the gC1q domain [31]. TNF-related apoptosis-inducing ligand (TRAIL) also inhibits cellcycle progression by T cells and mediates thymocyte apoptosis, and hence is important in the induction of autoimmunity [32]. Adiponectin has been shown to reverse insulin resistance associated with obesity by decreasing triglyceride content in the muscle and liver of obese mice [33,34]. This effect is mediated by activation of AMP-activated protein kinase (AMPK) and phosphorylation of acetyl-CoA carboxylase (ACC). Decreased adiponectin has been implicated in the development of insulin resistance in mouse models of obesity and type 2 diabetes [35]. A collagen-free form of ACRP30 has been shown to be present in serum, suggesting that full-length adiponectin can undergo proteolytic processing [33]. Interestingly, the gC1q domain of adiponectin can ameliorate hyperglycemia and hyperinsulinemia much more potently than full-length adiponectin [33]. TNF-a, a major secretory product of adipocytes, induces insulin resistance via NF-kB by interfering with an insulin-signaling mechanism: it inhibits tyrosine kinase activities of the insulin receptor and serine phosphorylation of insulin receptor substrate 1 [36]. TNF-a also contributes to insulin resistance by reducing the secretion of adiponectin by adipocytes [36]. By analogy, a set of hibernation proteins are downregulated in the serum of hibernating chipmunk, suggesting a role in energy homeostasis [37]. Analogous to the structural role of collagen VIII, a mild autosomal disorder associated with growth plate abnormalities, called ‘Schmid metaphyseal chondrodysplasia’, has been associated with missense mutations in the gC1q domain of collagen X which disrupt the hydrophobic core and perturb trimer assembly [16]. The receptor activator of NF-kB ligand has been linked with an autosomal dominant bone disease, ‘familial expansile osteolysis’, characterized by increased bone remodeling. Another genetic disease, called ‘hypohydrotic ectodermal dysplasia’, which is linked to ectodermal dysplasin (EDA), affects ectodermal tissue [22]. EDA is also required for the development of fish scales, suggesting a highly conserved function through evolution, reminiscent of saccular collagen, which probably has a vestibular function in the inner ear of the bluegill sunfish [38]. A Ser163 mutation to Arg163 in the gC1q domain of another C1q family member, CTRP5, has recently been associated with late-onset retinal degeneration [39]. The mutation causes formation of higher-order aggregates of the CTRP5 molecule, which leads to impairment of adhesion between retinal pigment epithelium (RPE) and Bruch’s membrane [39]. It is thus evident that the members of the C1q and TNF families have certain overlapping functions. This heralds exciting times ahead in the field, which could have significant implications for human health and disease. Perspectives and concluding remarks Members of the C1q and TNF superfamily are active as self-assembling non-covalent trimers whose individual www.sciencedirect.com


559

chains fold as compact ‘jelly-roll’ b-sandwiches. The topology and hydrophobic character of this b-core are conserved throughout both families. Sequence homology within the two families is relatively modest overall (w20–30% within the TNF family) but is high within the structurally conserved hydrophobic core and for residues responsible for trimer assembly through conserved hydrophobic surfaces. Sequence homology between the two families is low to the point of being undetectable. The internal structural homology is not mirrored on the surface of the proteins, with markedly different sequences and structures throughout both families in the loops which connect the conserved framework. In the TNF side of the superfamily, these differences give rise to diverse regions of contact between TNF and TNFR (3:3 stoichiometry) and contribute to the specific interaction with TNFR [20,40,41]. Such modes of ligand– receptor interaction have not been reported for the C1q family. Within the C1q family, the diversity of sequence and structure in the protruding loops, and hence of C1q–ligand interactions, is exemplified by the variability within C1q itself [3,11]. Although the overall trimeric structure appears to be central to the function of the TNF family, it is not yet clear that this is necessarily the case throughout the C1q family. It is also not known if any of the C1q family trimers engage the TNFR. The TNFR crossutilization (19 TNF ligands signal through 29 TNFRs) and crosstalk, which suggest an overlap in cell-signaling pathways, probably offer certain clues to future research aimed at the C1q family. The most ‘respected’ receptor for C1q, the calreticulin-CD91 complex, operates via the collagen region of C1q [42]. This interaction enhances p38 MAPK activation, NF-kB activity and production of proinflammatory cytokines and chemokines in macrophages [42]. Paradoxically, reduced NF-kB activity has been shown to be mediated by both gC1q and collagen regions using DCs [29], which points at the existence of a gC1q-specific receptor for C1q. The dichotomy of the gC1q–receptor interaction is further highlighted by two low- and highaffinity receptors for gC1q and full-length molecules of ACRP30, AdipoR1 and AdipoR2, which can mediate gC1q-stimulated AMPK, p38 MAPK activation and ACC phosphorylation [43]. Interestingly, AdipoR1 and AdipoR2 can form both homo- and heteromultimers, reminiscent of certain TNFRs [43]. Irrespective of the possibility of an evolutionary link between C1q and TNF families [5,20,41], the formation of a trimer with the ability to participate in protein–protein interactions through diverse external loops is well served by the adoption of a common core framework. The tenstranded b-sandwich core of the THD and gC1q domains provides not only the scaffolding for variable protruding loops and diverse functions but also the hydrophobic character required for formation and stabilization of the trimer. Given the involvement of the members of the C1q and TNF superfamily in such broad and diverse processes, it is tempting to envisage certain common themes that might unite their actions in different tissues, thereby justifying the evolutionary success of this superfamily. The TNF ligand family is well characterized in terms of

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receptor interaction, signal transduction pathways and effector and regulatory mechanisms. The C1q family seems to be a growing branch of the C1q and TNF superfamily tree, which requires rigorous dissection of its structure–function relationships and signaling pathways: clearly an area to watch in coming years. It is likely that the TNF family became more specialized and expanded during the process of orchestrating adaptive immunity [44], whereas C1q remained a versatile, scavenging innate immune molecule on the fringes of adaptive immunity. Whether an innate immune molecule like C1q has a TNF-related function, remains to be addressed. Acknowledgements We are funded by the European Commission (U.K., P.W., K.B.R.), the German National Genome Network (U.K.), the Alexander von Humboldt Foundation (U.K.), the Medical Research Council (K.B.R., R.B.S.), the Wellcome Trust (A.K.S., T.J.G.), the Commissariat a` l’Energie Atomique, the CNRS and the Universite´ Joseph Fourier, Grenoble (C.G., G.J.A.). We thank Rohit Ghai for his comments on the manuscript. We sincerely regret being unable to cite many seminal contributions due to restrictions on the number of references.

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