Epidermal growth factor-like domain repeat of stabilin-2 recognizes phosphatidylserine during cell corpse clearance.
Exposure of phosphatidylserine (PS) on the cell surface occurs early during apoptosis and serves as a recognition signal for phagocytes. Clearance of apoptotic cells by a membrane PS receptor is one of the critical anti-inflammatory functions of macrophages. However, the PS binding receptors and their recognition mechanisms have not been fully investigated. Recently, we reported that stabilin-2 is a PS receptor that mediates the clearance of apoptotic cells, thus releasing the anti-inflammatory cytokine, transforming growth factor beta. In this study, we showed that epidermal growth factor (EGF)-like domain repeats (EGFrp) in stabilin-2 can directly and specifically recognize PS. The EGFrps also competitively impaired apoptotic cell uptake by macrophages in in vivo models. We also showed that calcium ions are required for stabilin-2 to mediate phagocytosis via EGFrp. Interestingly, at least four tandem repeats of EGF-like domains were required to recognize PS, and the second atypical EGF-like domain in EGFrp was critical for calcium-dependent PS recognition. Considering that PS itself is an important target molecule for both apoptotic cells and nonapoptotic cells during various cellular processes, our results should help elucidate the molecular mechanism by which apoptotic cell clearance in the human body occurs and also have implications for targeting PS externalization of nonapoptotic cells.
Park
Seung-Yoon
SY
Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
Kim
So-Youn
SY
Jung
Mi-Yeon
MY
Bae
Dong-Jun
DJ
Kim
In-San
IS
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000187:drug effects; D010718:Phosphatidylserines / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment
D015816:Cell Adhesion Molecules, Neuronal; D010718:Phosphatidylserines; C449927:STAB2 protein, human; D002118:Calcium