Human galectin-2: novel inducer of T cell apoptosis with distinct profile of caspase activation.
Galectin-2 is structurally closely related to galectin-1, but has a distinct expression profile primarily confined to the gastrointestinal tract. Prominent differences in the proximal promoter regions between galectins-2 and -1 concern Sp1-, hepatocyte NF-3, and T cell-specific factor-1 binding sites. Of note, these sequence elements are positioned equally in the respective regions for human and rat galectins-2. Labeled galectin-2 binds to T cells in a beta-galactoside-specific manner. In contrast to galectin-1, the glycoproteins CD3 and CD7 are not ligands, while the shared affinity to beta1 integrin (or a closely associated glycoprotein) accounts for a substantial extent of cell surface binding. The carbohydrate-dependent binding of galectin-2 induces apoptosis in activated T cells. Fluorogenic substrate and inhibitor assays reveal involvement of caspases-3 and -9, in accordance with cleavage of the DNA fragmentation factor. Enhanced cytochrome c release, disruption of the mitochondrial membrane potential, and an increase of the Bax/Bcl-2 ratio by opposite regulation of expression of both proteins add to the evidence that the intrinsic apoptotic pathway is triggered. Cell cycle distribution and expression of regulatory proteins remained unaffected. Notably, galectins-1 and -7 reduce cyclin B1 expression, defining functional differences between the structurally closely related galectins. Cytokine secretion of activated T cells was significantly shifted to the Th2 profile. Our study thus classifies galectin-2 as proapoptotic effector for activated T cells, raising a therapeutic perspective. Of importance for understanding the complex galectin network, it teaches the lesson that selection of cell surface ligands, route of signaling, and effects on regulators of cell cycle progression are markedly different between structurally closely related galectins.
Sturm
Andreas
A
Medizinische Klinik mit Sektion Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany. andreas.sturm@charite.de
Lensch
Martin
M
André
Sabine
S
Kaltner
Herbert
H
Wiedenmann
Bertram
B
Rosewicz
Stefan
S
Dignass
Axel U
AU
Gabius
Hans-Joachim
HJ
D000818:Animals; D019011:Antigens, CD7 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D017252:CD3 Complex / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005697:Galactosides / Q000378:metabolism; D037483:Galectin 1 / Q000502:physiology; D037501:Galectin 2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D037161:Galectins / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007425:Intracellular Membranes / Q000502:physiology; D008213:Lymphocyte Activation / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D019011:Antigens, CD7; C494826:BAX protein, human; C494828:Bax protein, rat; D017252:CD3 Complex; D016207:Cytokines; D005697:Galactosides; D037483:Galectin 1; D037501:Galectin 2; D037161:Galectins; D019012:Integrin beta1; C092525:LGALS7 protein, human; C490488:Lgals7 protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C007816:beta-galactoside; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases