The conserved histidine in epidermal growth factor-like domains of stabilin-2 modulates pH-dependent recognition of phosphatidylserine in apoptotic cells.
Clearance of apoptotic cells is involved in the resolution of inflammation, and this mechanism is controlled by the regulation of pro- and anti-inflammatory cytokine production during the ingestion of apoptotic cells. Inflamed areas show extracellular acidity, and low pH stimulates cellular functions of immune cells. However, little is known about the influence of extracellular acidic pH on the function of phagocytic cells. In this study, we showed that stabilin-2-mediated phagocytosis is activated in low pH media (pH 6.8) and examined the molecular mechanisms underlying this pH-dependent enhancement of phagocytic activity. Stabilin-2, which is expressed in human monocyte derived macrophages (HMDM), is a phosphatidylserine (PS) receptor that mediates phagocytosis of apoptotic cells, and releases the anti-inflammatory cytokine, TGF-beta. The PS binding activity of stabilin-2 is enhanced in low pH, and a conserved histidine(1403) in close proximity to the PS binding loop is critical for pH-dependent activity. We propose that protonation of His(1403) may rearrange the PS binding loop to enhance binding affinity in low pH, indicating that acidic pH might act as a danger signal to stimulate stabilin-2-mediated phagocytosis to resolve inflammation. Considering that phosphatidylserine is an important target molecule for apoptotic cells in the acidic microenvironment of inflammation and tumors, our results also have implications for pH sensitive targeting of apoptotic cells.
Kim
Soyoun
S
Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
Bae
Dong-Jun
DJ
Hong
Mina
M
Park
Seung-Yoon
SY
Kim
In-San
IS
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000378:metabolism*; D017124:Conserved Sequence; D004815:Epidermal Growth Factor / Q000737:chemistry*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D005260:Female; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007739:L Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
D015816:Cell Adhesion Molecules, Neuronal; D010718:Phosphatidylserines; D006639:Histidine; D004815:Epidermal Growth Factor; D002118:Calcium