The immunoglobulin domain PRR family

The immunoglobulin domain plays a primary role in pattern recognition in the mammalian immune system. As a building block of antibodies, major histocompatibility complexes (MHCs), and other proteins that are responsible for making direct contact with pathogens, the immunoglobulin domain is evolutionarily engineered for the specific recognition and binding that is required for pattern recognition. Different subcategories of immuno-globulin domain may be recognized on the basis of sequence similarity, but the structure of the various domains tends to remain conserved within the superfamily. Immunoglobulin domains are characterized by a region of approximately 100 amino acids that fold to form two facing, anti-parallel P-sheets that interact with each other hydropho-bically while residues between these sheets bend outward. These intervening loops are available for ligand binding and can accommodate amino acid sequence changes without changing the conserved structure, thus allowing for a high degree of interaction specificity and diversity. This property gives these domains a propensity for contact-dependent functions (Williams and Barclay, 1988) and makes the immunoglobulin superfamily (IgSF) members ideal proteins for any process requiring adhesion and recognition, especially when a domain is repeated often or found adjacent to other highly interactive domains.

According to the broadest definition, the IgSF of any species contains genes encoding at least one immunoglobulin domain, as defined by a typical conserved sequence and structure. Although most thoroughly studied in mammals, immunoglobu-lin-domain-containing proteins in a wide range of species are responsible for recognizing invading pathogens as non-self and promoting their elimination via a range of immune mechanisms, both cellular and humoral. Here, we outline what is known about the pattern recognition and immune involvement of IgSF members in invertebrates. Invertebrates do not have antibodies, a MHC, or other prototypical immunoglobulin-containing immune molecules, yet they do have proteins that contain immunoglobulin domains and possess either putative or confirmed pattern-recognition capabilities. In some cases, these invertebrate IgSF members also have catalytic or signalling domains that can initiate an immune response in response to a pathogen, as is true for mammalian PRRs (such as antibodies).

Several individual invertebrate IgSF members have been analysed in terms of their recognition properties and immune relevance. Studies in Manduca sexta and Hyalophora cecropia (as well as other moths) have described hemolin, a protein previously known as P4 that contains five immunoglobulin domains and which is present in the haemolymph of both insects (Sun et al, 1990). Hemolin is transcriptionally induced by bacteria and seems to play a role in regulating cellular immune responses, such as the prevention of haemocyte aggregation and initiation of phagocytosis (Ladendorff and Kanost, 1991; Lanz-Mendoza et al, 1996). Since hemolin can bind bacteria and is specific for the lipid A moiety of lipopolysacchar-ide, it is considered a true PRR (Daffre and Faye, 1997; Yu and Kanost, 2002). In addition to its effect on aggregation and phagocytosis, hemolin is also important for phenoloxidase activity, suggesting that insects are highly dependent on this PRR for immune defence (Terenius et al, 2007). This conclusion is supported by the increased susceptibility of M. sexta to entomopathogenic bacteria that is seen when the hemolin gene is silenced by RNAi prior to bacterial infection (Eleftherianos et al, 2006b). Further experiments have suggested that hemo-lin is broadly specific for Gram-negative bacteria (Eleftherianos et al, 2006a, 2007).

A putative PRR, the molluscan defence molecule (MDM) of Lymnaea stagnalis, shares a five-immunoglobulin domain structure with and is similar in sequence to hemolin. This molecule is gradually downregulated as the infection of the mollusc with a schistosomal parasite progresses. Hoek and colleagues hypothesize that the expression of MDM is manipulated by the schistosome as a method to avoid immune surveillance (Hoek et al, 1996).

The Dscam of A. gambiae comprises tandem immunoglobulin domains and has been shown to be involved in the insect's defence against bacteria and Plasmodium parasites (Dong et al., 2006b). This remarkable protein is discussed further in section 5.6.

Identified via a bioinformatic and transcriptomic screen of the entire A. gambiae IgSF, the proteins known as infection responsive with immunoglobu-lin domain 3, 5, and 6 (IRID3, IRID5, and IRID6) are major players in the mosquito's defence against bacteria and Plasmodium parasites (see Figure 5.3 for IRID domain organization). RNAi-mediated silencing of IRID3 and IRID5 increases the mosquitoes' susceptibility to Gram-positive and -negative bacteria, while IRID3 silencing disrupts the bacterial load in the haemocoel. IRID6-depleted mosquitoes become more amenable to infection by both rodent and human malaria parasites. All three molecules are transcriptionally influenced by bacterial or parasitic infection. The ability of these molecules


-----mnnnnnnDo IRID3

innxnmninM>fli>0iHn]0D IRID4

| Ig | DUF1136 □ LDL B Laminin G ^Laminin B DEGF 1 Fn3 S/T Kinase : Transmembrane IIIIIIIIIII lHH Peroxidase

E3 Von Willebrand D LRR Amino acid backbone

Figure 5.3 Domain organization of the IRID members of the IgSF family of A. gambiae. The domains of six IgSF members of IRID family are shown; the thin horizontal black line indicates the length of each protein whereas lines and boxes indicate specific domains based on similarity to amino acid sequences of domains with known functions as predicted according to the SMART database. These representations illustrate the diversity of domain architecture present in the IgSF. Some members are large and complex (such as IRID4) while others are short and quite simple, containing only a single immunoglobulin (Ig) with perhaps one other domain (such as IRID1). DUF, domain of unknown function; EGF, epidermal growth factor; Fn3, fibronectin 3; LDL, low-density lipoprotein; LRR, leucine-rich repeat; S/T kinase, serine/threonine kinase.

to bind pathogen surfaces has yet to be verified, but their domain structure suggests that such an interaction is likely (Garver et al., 2008).

IRID3 shows a remarkable similarity to peroxi-nectin, a PRR described primarily in crayfish and black shrimp. Peroxinectin's domain architecture combines the binding activity of immunoglobu-lin domains with the enzymic activity of a perox-idase domain. Since this protein has been shown to enhance both phagocytosis and encapsulation, it is thought to be opsonic; pathogens are bound by the immunoglobulin domains, and effector mechanisms are activated at the site of binding by the peroxidase domain (Johansson et al, 1995; Sritunyalucksana et al., 2001).

First identified and characterized in Biomphalaria galabrata, fibrinogen-related proteins 3 and 7 (FREP3 and FREP7) each have two immunoglobu-lin domains of variable sequence in addition to the fibrinogen domains that are characteristic of the FREP family. Transcription of both proteins is elevated during infection with the trematode Echinostoma paraensei, and both can bind and precipitate parasite surface antigens. Correspondingly, sequence analysis suggests that the positive selection is acting on the immunoglobulin domains of both FREP3 and FREP7, while the fibrinogen domains are relatively conserved. Taken together, their binding ability and sequence data make a strong case for considering these two FREPs to be innate PRRs (Adema et al, 1997; Zhang et al, 2001). The fact that homologues of the FREP genes are also encoded by the Drosophila and Anopheles genomes suggests that these PRRs may be widely represented throughout the invertebrates (Wang et al, 2005).

The concept of the immunoglobulin domain as the functional part of a PRR that binds pathogens in both vertebrates and invertebrates is not surprising, since the structure of this domain is ideal for this role. What is surprising and not well understood is the evolution of these domains and the immune molecules in which they are found. Although they perform similar functions using the same domain, antibodies and other vertebrate immune molecules are not closely related, according to phylogenic analyses. In fact, invertebrate immune factors such as those described here are more closely related to molecules of both the invertebrate and vertebrate nervous systems than they are to molecules of vertebrate immune systems (Hughes, 1998). Conceptually, the requirements for neuronal wiring and pathogen recognition are similar, since both depend on the recognition of a specific pattern for protection and proper response (Parnes and Hunkapiller, 1987). This interrelationship is functionally evident in insects, in which such molecules as Dscam are involved in both immune-related and neuronal activity in A. gambiae and D. melanogaster (Schmucker et al., 2000; Watson et al, 2005; Dong et al, 2006b). Thus, pattern recognition is relevant not only to our understanding of the processes involved in immune defence but also to our understanding of the molecular evolution of multiple systems spanning diverse species.

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