Galig, a novel cell death gene that encodes a mitochondrial protein promoting cytochrome c release.
Galectin-3 internal gene (Galig) was recently identified as an internal gene transcribed from the second intron of the human galectin-3 gene that is implicated in cell growth, cell differentiation, and cancer development. In this study, we show that galig expression causes morphological alterations in human cells, such as cell shrinkage, cytoplasm vacuolization, nuclei condensation, and ultimately cell death. These alterations were associated with extramitochondrial release of cytochrome c, a known cell death effector. Furthermore, Bcl-xL co-transfection significantly reduced the release of cytochrome c induced by galig expression, suggesting a common pathway between the cytotoxic activity of galig and the anti-apoptotic activity of Bcl-xL. This antagonism was not observed upon co-transfection of Bcl-2 and galig. Galig encodes a mitochondrial-targeted protein named mitogaligin. Structure-activity relationship studies showed that the mitochondrial addressing of mitogaligin relies on an internal sequence that is required and sufficient for the release of cytochrome c and cell death upon cell transfection. Moreover, incubation of isolated mitochondria with peptides derived from mitogaligin induces cytochrome c release. Altogether, these results show that galig is a novel cell death gene encoding mitogaligin, a protein promoting cytochrome c release upon direct interaction with the mitochondria.
Duneau
Mélanie
M
Centre de Biophysique Moléculaire affiliated with the University of Orléans, CNRS UPR4301, Rue Charles Sadron, 45071 Orléans Cedex 02, France.
Boyer-Guittaut
Michaël
M
Gonzalez
Patrick
P
Charpentier
Stéphane
S
Normand
Thierry
T
Dubois
Martine
M
Raimond
Jacques
J
Legrand
Alain
A
D017304:Annexin A5 / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics*; D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry; D004926:Escherichia coli / Q000254:growth & development; D005091:Exons; D005434:Flow Cytometry; D037161:Galectins; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007438:Introns; D008156:Luciferases / Q000378:metabolism; D008845:Microinjections; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D017304:Annexin A5; D001798:Blood Proteins; D003574:Cytochrome c Group; D037161:Galectins; C428445:LGALS3 protein, human; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases