Transglutaminase 2 Is Needed for the Formation of an Efficient Phagocyte Portal in Macrophages Engulfing Apoptotic Cells

• Published in: The Journal of immunology (1950) Vol. 182; no. 4; pp. 2084 - 2092
• Main Authors: Toth, Beata, Garabuczi, Eva, Sarang, Zsolt, Vereb, Gyorgy, Vamosi, Gyorgy, Aeschlimann, Daniel, Blasko, Bernadett, Becsi, Balint, Erdodi, Ferenc, Lacy-Hulbert, Adam, Zhang, Ailiang, Falasca, Laura, Birge, Raymond B, Balajthy, Zoltan, Melino, Gerry, Fesus, Laszlo, Szondy, Zsuzsa
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.02.2009
• Subjects: Animals; Antigens, Surface - immunology; Antigens, Surface - metabolism; Apoptosis - immunology; Fluorescent Antibody Technique; GTP-Binding Proteins - genetics; GTP-Binding Proteins - immunology; GTP-Binding Proteins - metabolism; Integrin beta3 - immunology; Integrin beta3 - metabolism; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Knockout; Microscopy, Confocal; Milk Proteins - immunology; Milk Proteins - metabolism; Mutagenesis, Site-Directed; Phagocytosis - immunology; rac1 GTP-Binding Protein - immunology; rac1 GTP-Binding Protein - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - immunology; Transglutaminases - genetics; Transglutaminases - immunology; Transglutaminases - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0803444

Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin beta(3). We have previously shown that TG2(-/-) mice develop an age-dependent autoimmunity due to defective in vivo clearance of apoptotic cells. Here we report that TG2 on the cell surface and in guanine nucleotide-bound form promotes phagocytosis. Besides being a binding partner for integrin beta(3), a receptor known to mediate the uptake of apoptotic cells via activating Rac1, we also show that TG2 binds MFG-E8 (milk fat globulin EGF factor 8), a protein known to bridge integrin beta(3) to apoptotic cells. Finally, we report that in wild-type macrophages one or two engulfing portals are formed during phagocytosis of apoptotic cells that are characterized by accumulation of integrin beta(3) and Rac1. In the absence of TG2, integrin beta(3) cannot properly recognize the apoptotic cells, is not accumulated in the phagocytic cup, and its signaling is impaired. As a result, the formation of the engulfing portals, as well as the portals formed, is much less efficient. We propose that TG2 has a novel function to stabilize efficient phagocytic portals.