Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells.
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.
Tóth
Beáta
B
Department of Biochemistry and Molecular Biology, Apoptosis and Genomics Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
Garabuczi
Eva
E
Sarang
Zsolt
Z
Vereb
György
G
Vámosi
György
G
Aeschlimann
Daniel
D
Blaskó
Bernadett
B
Bécsi
Bálint
B
Erdõdi
Ferenc
F
Lacy-Hulbert
Adam
A
Zhang
Ailiang
A
Falasca
Laura
L
Birge
Raymond B
RB
Balajthy
Zoltán
Z
Melino
Gerry
G
Fésüs
László
L
Szondy
Zsuzsa
Z
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D039661:Integrin beta3 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008894:Milk Proteins / Q000276:immunology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010587:Phagocytosis / Q000276:immunology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D011503:Transglutaminases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
D000954:Antigens, Surface; D039661:Integrin beta3; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein