Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling.
Leukocytes from individuals with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency, and bearing a wild-type CXCR4 ORF (WHIM(WT)) display impaired CXCR4 internalization and desensitization upon exposure to CXCL12. The resulting enhanced CXCR4-dependent responses, including chemotaxis, probably impair leukocyte trafficking and account for the immunohematologic clinical manifestations of WHIM syndrome. We provided here evidence that GPCR kinase-3 (GRK3) specifically regulates CXCL12-promoted internalization and desensitization of CXCR4. GRK3-silenced control cells displayed altered CXCR4 attenuation and enhanced chemotaxis, as did WHIM(WT) cells. These findings identified GRK3 as a negative regulator of CXCL12-induced chemotaxis and as a candidate responsible for CXCR4 dysfunction in WHIM(WT) leukocytes. Consistent with this, we showed that GRK3 overexpression in both leukocytes and skin fibroblasts from 2 unrelated WHIM(WT) patients restored CXCL12-induced internalization and desensitization of CXCR4 and normalized chemotaxis. Moreover, we found in cells derived from one patient a profound and selective decrease in GRK3 products that probably resulted from defective mRNA synthesis. Taken together, these results have revealed a pivotal role for GRK3 in regulating CXCR4 attenuation and have provided a mechanistic link between the GRK3 pathway and the CXCR4-related WHIM(WT) disorder.
Balabanian
Karl
K
INSERM U819, Paris, France.
Levoye
Angélique
A
Klemm
Lysiane
L
Lagane
Bernard
B
Hermine
Olivier
O
Harriague
Julie
J
Baleux
Françoise
F
Arenzana-Seisdedos
Fernando
F
Bachelerie
Françoise
F
D000361:Agammaglobulinemia / Q000378:metabolism; D019390:Arrestins / Q000502:physiology; D001424:Bacterial Infections / Q000378:metabolism; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000502:physiology; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000235:genetics / Q000502:physiology*; D030342:Genetic Diseases, Inborn / Q000097:blood*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D009503:Neutropenia / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013577:Syndrome; D014860:Warts / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D000071557:beta-Arrestins; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human