Abstract
Galectin-1 (Gal-1) regulates leukocyte turnover by inducing the cell surface exposure of phosphatidylserine (PS), a ligand that targets cells for phagocytic removal, in the absence of apoptosis. Gal-1 monomer-dimer equilibrium appears to modulate Gal-1-induced PS exposure, although the mechanism underlying this regulation remains unclear. Here we show that monomer-dimer equilibrium regulates Gal-1 sensitivity to oxidation. A mutant form of Gal-1, containing C2S and V5D mutations (mGal-1), exhibits impaired dimerization and fails to induce cell surface PS exposure while retaining the ability to recognize carbohydrates and signal Ca(2+) flux in leukocytes. mGal-1 also displayed enhanced sensitivity to oxidation, whereas ligand, which partially protected Gal-1 from oxidation, enhanced Gal-1 dimerization. Continual incubation of leukocytes with Gal-1 resulted in gradual oxidative inactivation with concomitant loss of cell surface PS, whereas rapid oxidation prevented mGal-1 from inducing PS exposure. Stabilization of Gal-1 or mGal-1 with iodoacetamide fully protected Gal-1 and mGal-1 from oxidation. Alkylation-induced stabilization allowed Gal-1 to signal sustained PS exposure in leukocytes and mGal-1 to signal both Ca(2+) flux and PS exposure. Taken together, these results demonstrate that monomer-dimer equilibrium regulates Gal-1 sensitivity to oxidative inactivation and provides a mechanism whereby ligand partially protects Gal-1 from oxidation.
Highlights
FEBRUARY 20, 2009 VOLUME 284 NUMBER 8 inducing apoptotic cell death
Our results demonstrate that Gal-1 monomer-dimer equilibrium provides a key regulatory point controlling both Gal-1 sensitivity to oxidation and its ability to signal PS exposure in leukocytes
MGal-1 Induces Ca2ϩ Flux Yet Fails to Induce PS Exposure in HL60 Cells— Gal-1-induced PS exposure requires the induction of proximal signaling events, such as intracellular Ca2ϩ flux [6, 10], previous studies demonstrated that Gal1-induced PS exposure requires continuous engagement of
Summary
FEBRUARY 20, 2009 VOLUME 284 NUMBER 8 inducing apoptotic cell death. In contrast, several galectin family members, in particular galectin-1 (Gal-1),2 uniquely regulate neutrophil turnover by inducing phosphatidylserine (PS) exposure, which normally sensitizes apoptotic cells to phagocytic removal [3, 4], independent of apoptosis, a process recently termed preaparesis [5]. Our results demonstrate that Gal-1 monomer-dimer equilibrium provides a key regulatory point controlling both Gal-1 sensitivity to oxidation and its ability to signal PS exposure in leukocytes.
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