The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria

• Published in: Journal of leukocyte biology Vol. 97; no. 3; pp. 521 - 531
• Main Authors: Delgado Tasco´n, Julia, Adrian, Jonas, Kopp, Kathrin, Scholz, Philipp, Tschan, Mario P., Kuespert, Katharina, Hauck, Christof R.
• Format: Journal Article
• Language: English
• Published: England Society for Leukocyte Biology 01.03.2015
• Subjects: Amino Acid Sequence; Bacteria; Bacteria - metabolism; Carcinoembryonic Antigen - chemistry; Carcinoembryonic Antigen - genetics; Carcinoembryonic Antigen - metabolism; Cytoplasm - chemistry; Granulocytes - metabolism; HEK293 Cells; HL-60 Cells; Humans; ITAM; Molecular Sequence Data; Myeloid Cells - metabolism; Phagocytes - metabolism; Phagocytosis; Phosphorylation; Phosphotyrosine - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Receptors, Signal Transduction, & Genes; Signal Transduction; src Homology Domains; Src kinase; src-Family Kinases - metabolism; tyrosine phosphorylation; ITAM; Src kinase; tyrosine phosphorylation
• ISSN: 0741-5400; 1938-3673; 1938-3673
• DOI: 10.1189/jlb.2AB0813-449RR

CEACAM4 contains a functional immunoreceptor tyrosinebased activation motif, which is tyrosine‐phosphorylated, and initiates efficient phagocytosis of attached bacteria. Human granulocytes express several glycoproteins of the CEACAM family. One family member, CEACAM3, operates as a single‐chain phagocytic receptor, initiating the detection, internalization, and destruction of a limited set of gram‐negative bacteria. In contrast, the function of CEACAM4, a closely related protein, is completely unknown. This is mainly a result of a lack of a specific ligand for CEACAM4. By generating chimeric proteins containing the extracellular bacteria‐binding domain of CEACAM3 and the transmembrane and cytoplasmic part of CEACAM4 (CEACAM3/4) we demonstrate that this chimeric receptor can trigger efficient phagocytosis of attached particles. Uptake of CEACAM3/4‐bound bacteria requires the intact ITAM of CEACAM4, and this motif is phosphorylated by Src family PTKs upon receptor clustering. Furthermore, SH2 domains derived from Src PTKs, PI3K, and the adapter molecule Nck are recruited and associate directly with the phosphorylated CEACAM4 ITAM. Deletion of this sequence motif or inhibition of Src PTKs blocks CEACAM4‐mediated uptake. Together, our results suggest that this orphan receptor of the CEACAM family has phagocytic function and prompt efforts to identify CEACAM4 ligands.