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* Department of Biochemistry and Molecular Biology, Apoptosis and Genomics Research Group, Hungarian Academy of Sciences, Debrecen, Hungary;
Department of Biophysics and Cell Biology and
Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Research Center of Molecular Medicine, University of Debrecen, Debrecen, Hungary;
Matrix Biology and Tissue Repair Research Unit, Dental School, University of Wales College of Medicine, Cardiff, U.K.;
¶ 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary;
|| Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Research Center for Molecular Medicine, Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary;
# University of Edinburgh/Medical Research Council Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh, U.K.;
** Laboratory of Electron Microscopy, National Institute for Infectious Diseases, Institute for Cancer Research and Treatment "L. Spallanzani", Rome, Italy;
Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, New Jersey, NJ 07103;
* Fondazione S. Lucia, Roma, Italy and Medical Research Council, Toxicology Unit, Leicester, U.K.
Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin β3. 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 β3, 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 β3 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 β3 and Rac1. In the absence of TG2, integrin β3 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Hungarian grants from the National Research Fund (OTKA T T049445, TS-44798, F-67632) and the Ministry of Welfare (T 115/2006), as well as grants from the European Union (MRTN-CT-2006-036032, MRTN-CT-2006-035624, LSHB-CT-2007-037730) and Action Medical Research, U.K. (AP1043).
2 Address correspondence and reprint requests to Dr. Zsuzsa Szondy, Department of Biochemistry and Molecular Biology, University of Debrecen, Nagyerdei krt.98, H-4012 Debrecen, Hungary. E-mail address: szondy{at}indi.dote.hu
3 Abbreviations used in this paper: LRP, lipoprotein receptor-related receptor; CFDA, 6-carboxy-3',6'-diacetylfluorescein; CMTMR, 5-(and 6-)-(((4-chloromethyl)benzoyl)amino) tetramethylrhodamine; ELMO, engulfment and cell motility migration protein; MFG-E8, milk fat globulin EGF factor 8; TG2, transglutaminase 2; WT, wild type.
4 The online version of this article contains supplemental material.
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