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Identification of CXCL13 as an agonist and CXCL11 as an inverse agonist for the viral G protein-coupled receptor ORF74
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DOI：10.1016/j.bcp.2026.118313.png)
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Abstract
En 中文
Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes latent infection in humans, but under conditions of immune suppression, it may reactivate and contribute to severe diseases, including Kaposi’s sarcoma (KS) and B-cell malignancies. The KSHV genome encodes a single G protein-coupled receptor (GPCR), open reading frame 74 (ORF74), which shows homology to human chemokine receptors. Since its identification in 1996, ORF74 has subsequently been shown to interact with a broad range of human CXC chemokines, as well as CCL1 and the viral chemokine vCCL2. Compared with many human chemokine receptors, ORF74 displays high basal activity. These properties allow ORF74 to deregulate host cellular pathways through constitutive and chemokine-modulated signaling. In this study, we evaluated several human chemokines that, to our knowledge, had not previously been tested in ORF74-dependent cellular assays. Whereas CXCL9, CXCL14, CXCL16 and CXCL17 did not interact with ORF74, CXCL13 was identified as an additional ORF74 agonist and CXCL11 as an inverse agonist. CXCL13 dose-dependently induced ORF74-mediated Ca2+ release, β-arrestin1/2 recruitment and chemotaxis, and enhanced basal nuclear factor κB (NF-κB) activity in ORF74-expressing cells. In contrast, CXCL11 showed no detectable ORF74 agonist activity in the calcium mobilization or chemotaxis assay, but antagonized CXCL1-induced responses in both readouts. CXCL11 also elicited inverse agonist-like responses in β-arrestin1/2 recruitment assays and reduced basal NF-κB signaling. Our study thus reveals CXCL13 and CXCL11 as two additional chemokine ligands for ORF74, further expanding the pharmacological profile of this viral GPCR.
Keywords:
ORF74
CXCL13
CXCL11
Calcium mobilization
β-arrestin recruitment
NF-κB
Chemotaxis
ACKR5
atypical chemokine receptor 5
AF647
Alexa fluor 647
AUC
area under the curve
BAC
bacterial artificial chromosome
CCL
CC chemokine ligand
CCR
CC chemokine receptor
CXCL
CXC chemokine ligand
CXCR
CXC chemokine receptor
DMEM
Dulbecco’s modified Eagle medium
Emax
maximal effect
ELR
Glu-Leu-Arg
FBS
fetal bovine serum
GM-CSF
granulocyte–macrophage colony-stimulating factor
GPCR
G protein-coupled receptor
GRK
G protein-coupled receptor kinase
HBSS
Hank’s balanced salt solution
HHV8
human herpesvirus 8
IC50
half-maximal inhibitory concentration
KS
Kaposi’s sarcoma
KSHV
Kaposi’s sarcoma-associated herpesvirus
Max–Min
maximum minus minimum response
MFI
median fluorescence intensity
NanoBiT
NanoLuc binary technology
NF-κB
nuclear factor κB
ORF74
open reading frame 74
PI
phosphatidylinositol
pEC50
negative logarithm of the half-maximal effective concentration
pIC50
negative logarithm of the half-maximal inhibitory concentration
PLC
phospholipase C
RT
room temperature
STAT3
signal transducer and activator of transcription 3
TLR3
Toll-like receptor 3
VEGF
vascular endothelial growth factor
vFLIP
viral FLICE inhibitory protein
vGPCR
viral G protein-coupled receptor.
Journal
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5.6
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1.3W
Citations:
3.3W
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