Identification of the C3a receptor (C3AR1) as the target of the VGF-derived peptide TLQP-21 in rodent cells.
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.
Euroscreen SA, B-6041 Gosselies, Belgium.
Sebastien
S
Hannedouche
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Valerie
V
Beck
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Juliet
J
Leighton-Davies
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Martin
M
Beibel
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Guglielmo
G
Roma
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Edward J
EJ
Oakeley
Euroscreen SA, B-6041 Gosselies, Belgium.
Vincent
V
Lannoy
Euroscreen SA, B-6041 Gosselies, Belgium.
Jerome
J
Bernard
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Jacques
J
Hamon
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Samuel
S
Barbieri
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Inga
I
Preuss
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Marie-Christine
MC
Lasbennes
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Andreas W
AW
Sailer
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Thomas
T
Suply
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Klaus
K
Seuwen
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland.
Christian N
CN
Parker
From Novartis AG, Novartis Campus, CH-4056 Basel, Switzerland. Electronic address: frederic.bassilana@novartis.com.
Frederic
F
Bassilana
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D011951:Receptors, Complement / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013045:Species Specificity; D059467:Transcriptome / Q000187:drug effects
D009414:Nerve Growth Factors; D009479:Neuropeptides; D010446:Peptide Fragments; D011951:Receptors, Complement; C522412:TLQP-21 peptide; C510637:VGF protein, human; C512697:Vgf protein, mouse; C062040:Vgf protein, rat; C085567:complement C3a receptor; D037342:Pertussis Toxin
C3AR1; Cell Migration; Complement System; G Protein-coupled Receptors (GPCRs); Gene Silencing; Metabolism; RNA-Seq; Receptor Identification; TLQP-21