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    • br Origin of vertebrate CXC chemokine

    2020-07-27


    Origin of vertebrate CXC chemokine receptors The MK1775 of the vertebrate CXC chemokines and receptors has not been resolved. Based on the evolution of the immune system and central nervous system, Huising et al. proposed that primordial CXC chemokines and receptors developed first as regulators of neuron chemotaxis (Huising et al., 2003a) and have identified CXCL12/CXCR4 as the possible primordial molecules. This theory has been disputed by others because the CXCL12/CXCR4 orthologues are not found in the primitive chordate species such as amphioxus (Branchiostoma floridae) and sea squirt (Ciona intestinalis) which possess a central nerve system (Bajoghli, 2013, Holland, 2009, Nomiyama et al., 2011, Shields, 2003). After extensive sequence analysis, we found that three database entries (Ensembl Acc. Nos.: ENSCINP00000026710, ENSCINP00000013105 and ENSCINP00000030444) with moderate sequence homology to vertebrate chemokine receptors are present in the C. intestinalis genome (Table 2 and Supplementary file 5). Blastp analysis of these sequences gave top hits with relaxin/insulin-like family peptide receptor (RXFP) 3, angiotensin II receptor (AGTR), somatostatin receptor (SSTR), CCR and CXCR, suggesting a possible common origin. RXFP3, AGTR and SSTR bind to neuron-endocrine peptide ligands and regulate many physiological processes in animals, including reproduction, growth, the nervous system, food intake, inflammation and stress (Bathgate et al., 2013, Ferrario and Strawn, 2006, Tulipano and Schulz, 2007). It is notable that two of the three C. intestinalis molecules (Ensembl Acc. Nos.: ENSCINP00000013105 and ENSCINP00000030444) contain a DRY motif (DRWLAIV and DRYLAVV respectively) that is conserved in some GPCRs including chemokine receptors (Fig. 5). This motif is known to be required for G-protein coupling and downstream signalling (Graham et al., 2012, Wu et al., 2010). Intriguingly, the C. intestinalis RXFP3 orthologue also possesses the DRY motif (DRYMAVV, Fig. 5). Furthermore, chemokine receptors and some members of the RXFP3 and AGTR family members share cellular components such as arrestins, PI3K and extracellular regulated MAP kinase (ERK) 1/2 for signal transduction (Bathgate et al., 2013, van der Westhuizen et al., 2007). It is believed that the relaxin 3/RXFP3 system pre-dates the appearance of the chemokine system (Bathgate et al., 2013), and in humans CXCR4, ACKR3/CXCR7, CCR1 and CCR9 have been shown to be related to RXFP3 and RXFP4, AGTR, and formyl peptide receptors (FPR2 and FPR3) (Bathgate et al., 2013). In contrast to chordates, authentic chemokine and receptor orthologues can be found in the agnathan fishes (Bajoghli, 2013, Kuroda et al., 2003, Nomiyama et al., 2011, Nomiyama et al., 2013); sea lamprey has at least five chemokine receptor genes, one CXCR4 (Ensembl Acc. No.: ENSPMAP00000007678) (Kuroda et al., 2003, Zlotnik et al., 2006), two ACKR3s/CXCR7s (Ensembl Acc. Nos.: ENSPMAP00000011187 and ENSPMAP00000011401), one related to CXCR1/2, CCR6 and CCR9 (Ensembl Acc. No.: ENSPMAP00000011202) and one related to CXCR3 and CCR4 (Ensembl Acc. No., ENSPMAP00000011160) (Table 2). In river lamprey (Lampetra fluviatilis), an orthologue of CXCL8 has been characterised and is expressed in lymphocyte like cells (Najakshin et al., 1999), and its candidate receptor(s) could be one of the homologous receptor genes found in sea lamprey. Agnathans are proposed to have undergone the 1R whole genome duplication followed by an additional lineage specific genome duplication (Caputo Barucchi et al., 2013, Lagman et al., 2013, Mehta et al., 2013) and have a non-canonical adaptive immune system based upon leucine-rich repeat containing receptors (Cooper and Herrin, 2010). It can be hypothesised that the emergence of the chemokine system might be associated with this major evolutionary change in immune defences, to regulate the diverse populations of immune cells appearing at this time (DeVries et al., 2006). The co-appearance of CXCR4/ACKR3 and inflammatory CXCRs in agnathans suggests that CXCR4/ACKR3 and inflammatory chemokine receptors may have emerged as a result of the 1R whole genome duplication event (Fig. 4). Many CXCR genes in teleosts have been duplicated, by either the 3rd whole genome duplication that occurred in basal teleosts and/or random duplication; at least two copies of CXCR1, CXCR3, CXCR4 and ACKR3/CXCR7 genes are present (Fig. 1 and Supplementary file 4). Their subfunctionalization is expected to be complex.