Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived Peptide TLQP-21 in Rodent Cells

• Published in: The Journal of biological chemistry Vol. 288; no. 38; pp. 27434 - 27443
• Main Authors: Hannedouche, Sebastien, Beck, Valerie, Leighton-Davies, Juliet, Beibel, Martin, Roma, Guglielmo, Oakeley, Edward J., Lannoy, Vincent, Bernard, Jerome, Hamon, Jacques, Barbieri, Samuel, Preuss, Inga, Lasbennes, Marie-Christine, Sailer, Andreas W., Suply, Thomas, Seuwen, Klaus, Parker, Christian N., Bassilana, Frederic
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-09-2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Base Sequence; C3AR1; Cell Migration; Cell Movement - drug effects; CHO Cells; Complement System; Cricetinae; Cricetulus; G Protein-coupled Receptors (GPCRs); Gene Silencing; Genome-Wide Association Study; HEK293 Cells; Humans; Metabolism; Mice; Molecular Sequence Data; Nerve Growth Factors - pharmacology; Neuropeptides - pharmacology; Peptide Fragments - pharmacology; Pertussis Toxin - pharmacology; Rats; Receptor Identification; Receptors, Complement - agonists; Receptors, Complement - genetics; Receptors, Complement - metabolism; RNA-Seq; Signal Transduction - drug effects; Species Specificity; TLQP-21; Transcriptome - drug effects; Cell Migration; Complement System; TLQP-21; RNA-Seq; Gene Silencing; C3AR1; Receptor Identification; G Protein-coupled Receptors (GPCRs); Metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.497214

TLQP-21, a peptide derived from VGF (non-acronymic) by proteolytic processing, has been shown to modulate energy metabolism, differentiation, and cellular response to stress. Although extensively investigated, the receptor for this endogenous peptide has not previously been described. This study describes the use of a series of studies that show G protein-coupled receptor-mediated biological activity of TLQP-21 signaling in CHO-K1 cells. Unbiased genome-wide sequencing of the transcriptome from responsive CHO-K1 cells identified a prioritized list of possible G protein-coupled receptors bringing about this activity. Further experiments using a series of defined receptor antagonists and siRNAs led to the identification of complement C3a receptor-1 (C3AR1) as a target for TLQP-21 in rodents. We have not been able to demonstrate so far that this finding is translatable to the human receptor. Our results are in line with a large number of physiological observations in rodent models of food intake and metabolic control, where TLQP-21 shows activity. In addition, the sensitivity of TLQP-21 signaling to pertussis toxin is consistent with the known signaling pathway of C3AR1. The binding of TLQP-21 to C3AR1 not only has effects on signaling but also modulates cellular functions, as TLQP-21 was shown to have a role in directing migration of mouse RAW264.7 cells.
Background: TLQP-21 is a bioactive peptide for which the receptor(s) are unknown.
Results: We demonstrate that C3AR1 is a receptor for TLQP-21.
Conclusion: Many of the effects of TLQP-21 can be explained by C3AR1 activation.
Significance: These results provide a bridge linking the regulation of metabolism and the activation of complement in rodents.