Origin and evolution of TNF and TNF receptor superfamilies
Introduction
The tumor necrosis factor superfamily (TNFSF) and the TNF receptor superfamily (TNFRSF) are instrumental in a number of cellular signaling pathways involving inflammation, apoptosis, lymphocyte homeostasis, and tissue development (Bodmer et al., 2002, Ware, 2003). TNFSF ligands are type II membrane proteins that have an intracellular N terminus and an extracellular C terminus. The majority of these ligands are membrane bound, and about half of the different ligands encode proteolytic cleavage sites that can generate soluble forms that retain biological activity (Locksley et al., 2001). The TNF homology domain (THD) is located in the C terminus and is weakly conserved (20–30%) between ligand members. The signature THD is composed of 10 β-strands, which ultimately fold to form a compact “jellyroll” topology. Three monomers join to form a stable conical trimeric protein which is then able to initiate signaling through its respective receptor(s) (Bodmer et al., 2002). The LTA gene product is unusual as it can either form a homotrimer known as lymphotoxin-α (LTα also referred to as TNFβ) or it can form a heterotrimer with the lymphotoxin-β gene product resulting in either a α1β2 or α2β1 stoichiometry (Orlinick and Chao, 1998). The family wide tri-fold design produces more contacts between ligand and receptor than occurs with dimers which may lead to higher avidity (Locksley et al., 2001). Commonly, the trimeric ligand binds three monomeric receptors, which is essential for the initiation of the signaling pathway (Bossen et al., 2006). Mouse Tnfsf18 (Gitrl), one of the smallest ligands (125 aa) is unusual as it also associates as a homodimer that has reduced biological activity indicating the potential for alternative oligomerization which may modulate biological function of some ligand members (Chattopadhyay et al., 2008, Zhou et al., 2008). Human TNFSF ligand members are found clustered on the four MHC-paralogous chromosomes: Chr 1 (TNFSF4, TNFSF18, and FASLG), Chr 6 (LTB, TNF and LTA), Chr 9 (TNFSF15 and TNFSF8) and Chr 19 (TNFSF9, CD70 and TNFSF14). The remaining genes are found on chromosomes X (EDA and CD40LG), Chr 3 (TNFSF10), Chr 13 (TNFSF13B and TNFSF11) and Chr 17 (TNFSF13 and TNFSF12). A total of 29 receptor genes have been identified in humans that are dispersed across 14 chromosomes. In this review, we utilize standardized HGNC (human), MGI (Mouse) and ZFIN (Zebrafish) gene and protein nomenclature, but also include original annotation often utilized within the primary literature when it differs from the standardized nomenclature. The reader is also referred to a full list of mammalian gene names and alternative naming of TNFSF and TNFRSF members that can be found at (www.genenames.org) and the reader is also referred to a recent review of mammalian TNFSF and TNFRSF and the schematic depiction of ligand–receptor interacting combinations (Tansey and Szymkowski, 2009). Table 1 summarizes the known invertebrate and teleost fish TNFSF and TNFRSF genes.
The mammalian TNFRSF largely consist of type I transmembrane proteins that have extracellular N terminus and an intracellular C terminus. A few receptors encoded by genes TNFRSF13C, TNFRSF17, TNFRSF13B, and EDA2R are Type III transmembrane proteins and are signal peptide deficient. Members of the receptor family encoded by genes TNFSF11B and TNFRSF6B may also exist in soluble forms by proteolytic cleavage or by alternative splicing (Bodmer et al., 2002). TNFRSF structures are elongated and their extracellular domains usually contain one to four hallmark cysteine-rich domains (CRDs). CRDs are pseudo-repeats that consist of around 40 amino acids which contain six conserved cysteines that form three disulfide bonds upon folding. The elongated structure created by the positioning of disulfide bonds is vital in facilitating the receptor chains to fit the furrows of the trimeric ligand (Bodmer et al., 2002, Locksley et al., 2001).
Many invertebrate and vertebrate genomes are now available; and with the help of expressed sequence tag (EST) and Basic Local Alignment Search Tool (BLAST) analyses, the discovery of TNFSF and TNFRSF orthologues and paralogues has greatly increased. Genome mining provides further knowledge of the evolutionary history and potential insight into functional roles of these effecter proteins. In this review, we summarize recent research on the evolution of TNFSF members, their identification and characterization in invertebrates and non-mammalian vertebrates, with emphasis on teleost TNFSF and TNFRSF members.
Section snippets
TNFSF ligand and receptor evolution parallels whole genome duplication
The emergence of the adaptive immune system is thought to be linked to whole genome duplication events that occurred several times during vertebrate evolution (Flajnik and Kasahara, 2010, Kasahara, 2010). Fig. 1 shows major animal phyla and the putative rounds (R) of whole genome duplication as well as the numbers of currently described TNFSF and TNFRSF genes. There is a general correlation between numbers of TNFSF and TNFRSF and the rounds of genome duplication. However, it should be noted
Invertebrate TNFSF ligands and receptors
The best characterized ligand–receptor system in invertebrates has been described in fruit flies, where Eiger (ligand) binds to Wengen (receptor). Eiger is a type II transmembrane protein with a C-terminal THD (Moreno et al., 2002). Eiger is predominantly expressed in the nervous system, and where expressed in the eye, induces cell death and complete eye loss by a well defined pathway (Moreno et al., 2002, Igaki et al., 2002, Narasimamurthy et al., 2009). Similar to many other TNFSF, the
Teleost TNF-ligands and receptors
In an effort to better understand the evolution of TNFSF superfamily, we previously reported a bioinformatic search of teleost EST and genomic databases for orthologues and paralogues. Seventy-one teleost sequences were assimilated that contain a predicted TNF homology domain and forty-four had not been previously reported (Glenney and Wiens, 2007). Phylogenetic and synteny analyses determined that in addition to TNFα, teleosts: (1) possess orthologues of the human genes TNFSF13B (BAFF),
Teleost homologues of TNF and receptor TNFR1 (TNFRSF1A)
TNF gene homologues have been identified in a wide variety of fish species (Covello et al., 2009, Garcia-Castillo et al., 2002, Grayfer et al., 2008, Hirono et al., 2000, Kadowaki et al., 2009, Laing et al., 2001, Morrison et al., 2007, Nascimento et al., 2007, Ordas et al., 2007, Saeij et al., 2003, Savan and Sakai, 2004, Xiao et al., 2007, Xie et al., 2008, Zou et al., 2002) and an excellent review describes fish TNF gene sequence, exon structure and early experiments testing bioactivity of
Bioactivity of the TNFa pathway
Extensive in vivo functional analyses of the TNF pathway have been carried out in zebrafish. Injection of adult zebrafish i.m. with an expression construct for the precursor form of zebrafish TNF induced recruitment of neutrophils at 4 and 8 days (Roca et al., 2008). Surprisingly, i.p. injection of rZfTNF resulted in increased mortality of fish infected by viral challenge with Spring Viremia of Carp Virus. Cytokine expression indicated that rzfTNF-injected fish had slightly higher mRNA levels
Other TNFSF members in teleosts
In mammals, the TNF gene is flanked by two other genes LTB and LTA (Fig. 2A). Initial examination of the fish TNF locus failed to identify adjacent genes (Goetz et al., 2004), and it was a surprise when a novel TNF gene (TNF-N) was described next to TNF in both in fugu, Takifugu rubripes, and zebrafish, Danio rerio (Savan et al., 2005). The orientation of TNF-N is similar to LTA in mammals (Fig. 2C); however, phylogenetic analyses consistently group mammalian proteins TNFα and LTα together
Amphibian and avian TNF-ligands and receptors
In amphibians, a number of TNFSF ligands and receptor genes have been predicted from the Xenopus tropicalis genome; however, only a handful have been further characterized and functionally analyzed, and these have been primarily from X. laevis (Fig. 1). A TNFSF member (xTNF-α) and its receptor (xTNFR1) were characterized in X. laevis, and showed moderate sequence conservation with mammalian TNF-α via structural and phylogenetic analysis (Mawaribuchi et al., 2008). The THD of xTNF-α shared 34%
Future perspectives
Genome and EST database mining has identified many TNFSF and TNFRSF in chordates and lower vertebrates that have similarity to mammalian genes/proteins. A proposal to sequence 10,000 vertebrate genomes includes a number of fish species (n = 4246), that if completed, promises to dramatically expand the fish species available for computational analyses (Scientists GKCo, 2009). While gene discovery is likely to proceed rapidly, few gene products have been analyzed either at the molecular or
Acknowledgements
We apologize to all authors that we were not able to cite due to space limitations. This work was supported by Agricultural Research Service CRIS Project 1930-32000-005 “Integrated Approaches for Improving Aquatic Animal Health in Cool and Cold Water Aquaculture”. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture. USDA is an equal
References (99)
- et al.
Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota
Cell Host Microbe
(2007) - et al.
Mechanisms of nonspecific cytotoxic cell regulation of apoptosis: cytokine-like activity of Fas ligand
Fish Shellfish Immunol.
(2002) - et al.
Molecular cloning and expression of a TNF receptor and two TNF ligands in the fish ovary
Comp. Biochem. Physiol. B Biochem. Mol. Biol.
(2001) - et al.
The molecular architecture of the TNF superfamily
Trends Biochem. Sci.
(2002) - et al.
Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human
J. Biol. Chem.
(2006) - et al.
TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts
Blood
(2008) - et al.
Characterization and expression analysis of TNF-related apoptosis inducing ligand (TRAIL) in grass carp Ctenopharyngodon idella
Vet. Immunol. Immunopathol.
(2006) - et al.
Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death
Immunity
(2008) - et al.
A co-evolution perspective of the TNFSF and TNFRSF families in the immune system
Trends Immunol.
(2003) - et al.
Cloning and expression analysis of three striped trumpeter (Latris lineata) pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-8, in response to infection by the ectoparasitic, Chondracanthus goldsmidi
Fish Shellfish Immunol.
(2009)
First molluscan TNF-alpha homologue of the TNF superfamily in disk abalone: molecular characterization and expression analysis
Fish Shellfish Immunol.
A novel Fas ligand in mollusk abalone: molecular characterization, immune responses and biological activity of the recombinant protein
Fish Shellfish Immunol.
Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice
Immunity
Tumor necrosis factors
Dev. Comp. Immunol.
Molecular characterization of tumor necrosis factor receptors 1 and 2 of the goldfish (Carassius aurutus L.)
Mol. Immunol.
Characterization and functional analysis of goldfish (Carassius auratus L.) tumor necrosis factor-alpha
Dev. Comp. Immunol.
Differential expression profiles and gene structure of two tumor necrosis factor-alpha variants in Atlantic salmon (Salmo salar L.)
Mol. Immunol.
The immune gene repertoire encoded in the purple sea urchin genome
Dev. Biol.
TNF induces the growth of thymocytes in rainbow trout
Dev. Comp. Immunol.
Two types of tumor necrosis factor-alpha in bluefin tuna (Thunnus orientalis) genes: molecular cloning and expression profile in response to several immunological stimulants
Fish Shellfish Immunol.
Wengen, a member of the Drosophila tumor necrosis factor receptor superfamily, is required for Eiger signaling
J. Biol. Chem.
Host-microbe interactions in the developing zebrafish
Curr. Opin. Immunol.
Identification and expression analysis of lymphotoxin-beta like homologues in rainbow trout Oncorhynchus mykiss
Mol. Immunol.
Regulation of primitive hematopoiesis in zebrafish embryos by the death receptor gene
Exp. Hematol.
First molluscan TNFR homologue in Zhikong scallop: molecular characterization and expression analysis
Fish Shellfish Immunol.
Molecular cloning, functional characterization and phylogenetic analysis of B-cell activating factor in zebrafish (Danio rerio)
Fish Shellfish Immunol.
The TNF and TNF receptor superfamilies: integrating mammalian biology
Cell
A novel gene of tumor necrosis factor ligand superfamily from kuruma shrimp, Marsupenaeus japonicus
Fish Shellfish Immunol.
Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily
Curr. Biol.
Molecular cloning and expression analysis of tumour necrosis factor-alpha in amoebic gill disease (AGD)-affected Atlantic salmon (Salmo salar L.)
Fish Shellfish Immunol.
Molecular cloning and expression analysis of sea bass (Dicentrarchus labrax L.) tumor necrosis factor-alpha (TNF-alpha)
Fish Shellfish Immunol.
Turbot TNFalpha gene: molecular characterization and biological activity of the recombinant protein
Mol. Immunol.
TNF-related ligands and their receptors
Cell Signal.
Bioactivities of a tumour necrosis-like factor released by chicken macrophages
Dev. Comp. Immunol.
The genomic underpinnings of apoptosis in Strongylocentrotus purpuratus
Dev. Biol.
Molecular and functional characterization of carp TNF: a link between TNF polymorphism and trypanotolerance?
Dev. Comp. Immunol.
Tumour necrosis factor (TNF)alpha as a regulator of fat tissue mass in the Mediterranean gilthead sea bream (Sparus aurata L.)
Comp. Biochem. Physiol. B Biochem. Mol. Biol.
Presence of multiple isoforms of TNF alpha in carp (Cyprinus carpio L.): genomic and expression analysis
Fish Shellfish Immunol.
Fish scale development: hair today, teeth and scales yesterday?
Curr. Biol.
Xenopus death receptor-M1 and -M2, new members of the tumor necrosis factor receptor superfamily, trigger apoptotic signaling by differential mechanisms
J. Biol. Chem.
Tumor necrosis factor-related apoptosis-inducing ligand 1 (TRAIL1) enhances the transition of red blood cells from the larval to adult type during metamorphosis in Xenopus
Blood
The TNF superfamily in 2009: new pathways, new indications, and new drugs
Drug Discov. Today
The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans
Cell
The TNF superfamily
Cytokine Growth Factor Rev.
Tumor necrosis factor-alpha gene from mandarin fish, Siniperca chuatsi: molecular cloning, cytotoxicity analysis and expression profile
Mol. Immunol.
Bbt-TNFR1 and Bbt-TNFR2, two tumor necrosis factor receptors from Chinese amphioxus involve in host defense
Mol. Immunol.
Evolution by gene duplication: an update
Trends Ecol. Evol.
A novel tumor necrosis factor ligand superfamily member (CsTL) from Ciona savignyi: molecular identification and expression analysis
Dev. Comp. Immunol.
Differential expression of two tumor necrosis factor genes in rainbow trout, Oncorhynchus mykiss
Dev. Comp. Immunol.
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Both authors contributed equally to this review.