Galectin-1 induced activation of the mitochondrial apoptotic pathway: evidence for a connection between death-receptor and mitochondrial pathways in human Jurkat T lymphocytes.
Galectin-1 (gal-1) triggers T cell death by several distinct intracellular pathways including the activation of the death-receptor pathway. The aim of this study was to investigate whether gal-1 induced activation of the death-receptor pathway in Jurkat T lymphocytes mediates apoptosis via the mitochondrial pathway linked by truncated Bid (tBid). We demonstrate that gal-1 induced proteolytic cleavage of the death agonist Bid, a member of the Bcl-2/Bcl-xL family and a substrate of activated caspase-8, was inhibited by caspase-8 inhibitor II (Z-IETD-FMK). Downstream of Bid, gal-1 stimulated mitochondrial cytochrome c release as well as the activation and proteolytic processing of initiator procaspase-9 were effectively decreased by caspase-8 inhibitor II. Blocking of gal-1 induced cleavage of effector procaspase-3 by caspase-8 inhibitor II as well as by caspase-9 inhibitors I (Z-LEHD-FMK) and III (Ac-LEHD-CMK) indicates that receptor and mitochondrial pathways converged in procaspase-3 activation and contribute to proteolytic processing of effector procaspase-6 and -7. Western blot analyses and immunofluorescence staining revealed that exposure of Jurkat T cells to gal-1 resulted in the cleavage of the DNA-repair enzyme poly (ADP-ribose) polymerase, cytoskeletal alpha-fodrin, and nuclear lamin A as substrates of activated caspases. Our data demonstrate that Bid provides a connection between the death receptor and the mitochondrial pathway of gal-1 induced apoptosis in human Jurkat T lymphocytes.
Lange
Falko
F
Medical Faculty, Institute of Medical Biochemistry and Molecular Biology, Schillingallee 70, Rostock, Germany.
Brandt
Bettina
B
Tiedge
Markus
M
Jonas
Ludwig
L
Jeschke
Udo
U
Pöhland
Ralf
R
Walzel
Hermann
H
D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D037483:Galectin 1 / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D034904:Lamin Type A / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013049:Spectrin
D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D020169:Caspases; D045304:Cytochromes c; D037483:Galectin 1; D034904:Lamin Type A; D008840:Microfilament Proteins; D009842:Oligopeptides; D011065:Poly(ADP-ribose) Polymerases; D013049:Spectrin; C494814:BID protein, human; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone