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Review
. 2022 May 31:10:911414.
doi: 10.3389/fcell.2022.911414. eCollection 2022.

Molecular Structure, Expression and Role of TAFA4 and its Receptor FPR1 in the Spinal Cord

Sipin Zhu  1   2 , Xiaoyong Hu  3 , Samuel Bennett  2 , Yuliang Mai  3 , Jiake Xu  1   2
Affiliations
Review

Molecular Structure, Expression and Role of TAFA4 and its Receptor FPR1 in the Spinal Cord

Sipin Zhu et al. Front Cell Dev Biol. .

Abstract

TAFA chemokine like family member 4 (TAFA4, also named FAM19A4) is a member of the TAFA chemokine like ligand or FAM19A family, which includes TAFA1, TAFA2, TAFA3, TAFA4, and TAFA5 (or FAM19A1, FAM19A2, FAM19A3, FAM19A4, and FAM19A5). They are also referred to as neurokines and are involved in the regulation of a diverse range of cellular processes, including chemotaxis of macrophages, phagocytosis, and release of reactive oxygen species (ROS). TAFA4 is a marker of C-low-threshold mechanoreceptors and is expressed predominantly in nociceptors, such as dorsal root ganglia (DRG). TAFA4 has been implicated in the sensory perception of pain in the spinal cord. Mice with deficiency of TAFA4 demonstrate altered excitability in lamina IIi neurons in DRG in addition to increased mechanical and chemical nociception following inflammation or injury. As a secreted protein, TAFA4 binds to cell surface receptor formyl peptide receptor 1 (FPR1), a G protein-coupled receptor to mediate the chemoattraction of macrophages, phagocytosis, and the inflammatory profile of macrophages. It also interacts with cell surface neurexin to mediate signalling across the synapse. Further understanding the mechanisms by which this conserved protein family regulates diverse biological processes such as in neuronal functions, inflammation, and tissue fibrosis will help to design therapeutic targets for the treatment of TAFA related diseases such as spinal cord injury and neuro-inflammatory disorders.

Keywords: FAM19A; FPR1; TAFA4; chemotaxis; dorsal root ganglia; macrophages; signaling; spinal cord.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Multiple sequence alignment of TAFA4 in various species. (A) Multiple sequence alignment analyses show that TAFA4 shares sequence identity and similarity with TAFA4 homologues among various species including human, mouse, cynomolgus monkey, rat, chimpanzee, and dog (https://www.uniprot.org/align). (B) A family tree of TAFA4 homologue proteins is elucidated.
FIGURE 2
FIGURE 2
Multiple sequence alignment of TAFA4 among family members. (A) Multiple sequence analysis demonstrates that human TAFA1, TAFA2, TAFA3, TAFA4, and TAFA5 shares significant degree of amino acid sequence identity, especially at their C terminal regions. (B) Family tree of human TAFA1, TAFA2, TAFA3, TAFA4, and TAFA5.
FIGURE 3
FIGURE 3
Bioinformatic analysis of TATF 4 gene expression. (A) Gene expression of TAFA4 by BioGPS analyses (http://biogps.org/) and (B) by Euxassay analysis of embryonic tissue of day 14.5 (http://www.informatics.jax.org/image/MGI:4517366).
FIGURE 4
FIGURE 4
Molecular structural analysis of TAFA4. Molecular structure of TAFA4, predicted by bioinformatics information based on Uniprot (https://www.uniprot.org/), showing (A) a characteristic of a chemokine like ligand, (B) the Phyre2 web portal (http://www.sbg.bio.ic.ac.uk/phyre2/), and (C) AlphaFold web portal (https://alphafold.ebi.ac.uk/).
FIGURE 5
FIGURE 5
Multiple sequence alignment of FPR1. (A) Multiple sequence alignment analyses show that FPR1 shares sequence identity and similarity with FPR1 homologues among various species including human, mouse, chimpanzee, Rhesus macaque, rat, and rabbit (https://www.uniprot.org/align). (B) A family tree of FRP1 homologue proteins is elucidated.
FIGURE 6
FIGURE 6
Comparative sequence alignment of FPR1and FPR2. Multiple sequence analysis demonstrates that human FRP1 and FPR2 share significant degree of amino acid sequence identity.
FIGURE 7
FIGURE 7
Molecular structural analysis of FPR1. Molecular structure of FPR1, predicted by bioinformatics information based on (A) Uniprot (https://www.uniprot.org/), (B,C) the Phyre2 web portal (http://www.sbg.bio.ic.ac.uk/phyre2/) all showing characteristics of G protein-coupled receptor.
FIGURE 8
FIGURE 8
Molecular structural analysis of FPR2. Molecular structure of FPR2, predicted by bioinformatics information based on (A) Uniprot (https://www.uniprot.org/), (B,C) the Phyre2 web portal (http://www.sbg.bio.ic.ac.uk/phyre2/) all showing characteristics of G protein-coupled receptor.
FIGURE 9
FIGURE 9
3D structural images of FRP1 and FPR2. 3D structure of FRP1 and FPR2, predicted by (A) the Phyre2 web portal (http://www.sbg.bio.ic.ac.uk/phyre2/), (B) 3D structure of FRP1 and (C) FPR2 predicted by AlphaFold web portal (https://alphafold.ebi.ac.uk/).
FIGURE 10
FIGURE 10
Gene expression profiling of FPR1 and FPR2. mRNA expression profiling of FPR1 (A) and FPR2 (B) gene in human tissues and cells predicted by Genevisible® bioinformatics tool (http://genevisible.com), with the ten most highly ranking mRNA express levels, respectively.
FIGURE 11
FIGURE 11
TAFA4 and its receptors interaction. (A) TAFA4is expressed in DRG, retina and hypothalamus. (B) TAFA4 binds FPR1 and activates signalling pathways of Akt phosphorylation, calcium mobilization, and ROS release, leading to various cellular activities. In addition, TAFA4 binds cell surface neurexin and mediates synapse homeostasis.
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