The C-type lectin receptor CLECSF8 (CLEC4D) is expressed by myeloid cells and triggers cellular activation through Syk kinase.
CLECSF8 is a poorly characterized member of the "Dectin-2 cluster" of C-type lectin receptors and was originally thought to be expressed exclusively by macrophages. We show here that CLECSF8 is primarily expressed by peripheral blood neutrophils and monocytes and weakly by several subsets of peripheral blood dendritic cells. However, expression of this receptor is lost upon in vitro differentiation of monocytes into dendritic cells or macrophages. Like the other members of the Dectin-2 family, which require association of their transmembrane domains with signaling adaptors for surface expression, CLECSF8 is retained intracellularly when expressed in non-myeloid cells. However, we demonstrate that CLECSF8 does not associate with any known signaling adaptor molecule, including DAP10, DAP12, or the FcRγ chain, and we found that the C-type lectin domain of CLECSF8 was responsible for its intracellular retention. Although CLECSF8 does not contain a signaling motif in its cytoplasmic domain, we show that this receptor is capable of inducing signaling via Syk kinase in myeloid cells and that it can induce phagocytosis, proinflammatory cytokine production, and the respiratory burst. These data therefore indicate that CLECSF8 functions as an activation receptor on myeloid cells and associates with a novel adaptor molecule. Characterization of the CLECSF8-deficient mice and screening for ligands using oligosaccharide microarrays did not provide further insights into the physiological function of this receptor.
Institute of Infectious Disease and Molecular Medicine, Central Laboratory Services, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa.
Lisa M
LM
Graham
Vandana
V
Gupta
Georgia
G
Schafer
Delyth M
DM
Reid
Matti
M
Kimberg
Kevin M
KM
Dennehy
William G
WG
Hornsell
Reto
R
Guler
Maria A
MA
Campanero-Rhodes
Angelina S
AS
Palma
Ten
T
Feizi
Stella K
SK
Kim
Peter
P
Sobieszczuk
Janet A
JA
Willment
Gordon D
GD
Brown
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D009928:Organ Specificity; D010587:Phagocytosis; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016897:Respiratory Burst; D015398:Signal Transduction; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C482593:CLEC4D protein, human; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse