The conserved histidine in epidermal growth factor-like domains of stabilin-2 modulates pH-dependent recognition of phosphatidylserine in apoptotic cells

Soyoun Kim, Dong Jun Bae, Mina Hong, Seung Yoon Park, In-San Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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-β. 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.

Original languageEnglish
Pages (from-to)1154-1163
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume42
Issue number7
DOIs
Publication statusPublished - 2010 Jul 1
Externally publishedYes

Keywords

  • Apoptotic cell
  • Extracellular low pH
  • Phagocytosis
  • Phosphatidylserine
  • Stabilin-2

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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