The human septin7 and the yeast CDC10 septin prevent Bax and copper mediated cell death in yeast.
The mechanisms of programmed cell death activate genetically encoded intracellular programs in a controlled manner, the most common form being apoptosis. Apoptosis is carried out through a cascade of caspase mediated proteolytic cleavages initiated by the oligomerization of Bax, a cardinal regulator of mitochondrial-mediated apoptosis. Heterologous expression of Bax in yeast causes cell death that shares a number of similarities to processes that occur in mammalian apoptosis. A screen of a cardiac cDNA library for suppressors of Bax-mediated apoptosis identified human septin7, a protein that belongs to the septin superfamily of conserved GTP-binding proteins that share a conserved cdc/septin domain. Analysis of the amino acid sequence deduced from the septin7 clone as well as the corresponding human septin7 gene revealed that a novel alternatively spliced transcript called septin7 variant4 (v4) was uncovered. Yeast cells overexpressing the human septin7 v4 cDNA were also capable of resisting copper-mediated cell death suggesting that it is not only a Bax suppressor but also an anti-apoptotic sequence. Analysis of septin7 function in a MCA1Δ yeast strain suggests that septin7 inhibits apoptosis in a caspase independent pathway. Overexpression of the yeast septin7 ortholog CDC10 also conferred resistance to the negative effects of copper as well as protecting cells from the overexpression of Bax. In contrast, septin7 was unable to prevent the increase in cell size associated with mutants lacking the endogenous yeast CDC10 gene. Taken together, our analysis suggests that anti-apoptosis is a novel yet evolutionarily conserved property of the septin7 sub-family of septins.
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Avital
A
Horowitz
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Jason F
JF
Lapointe
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada.
Rawan
R
Eid
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Sara
S
Sheibani
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada.
Nada
N
Gharib
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada.
Natalie K
NK
Jones
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada.
Hojatollah
H
Vali
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
Craig A
CA
Mandato
Department of Chemistry and Chemical Engineering, Royal Military College, Kingston, Ontario, Canada. Electronic address: michael.greenwood@rmc.ca.
Michael T
MT
Greenwood
D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D020169:Caspases / Q000172:deficiency / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000633:toxicity*; D025141:Drug Resistance, Fungal / Q000187:drug effects; D005091:Exons / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D058112:Septins / Q000737:chemistry / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D029701:Saccharomyces cerevisiae Proteins; D051028:bcl-2-Associated X Protein; D003300:Copper; D020169:Caspases; C512892:CDC10 protein, S cerevisiae; D020558:GTP Phosphohydrolases; C113158:SEPTIN7 protein, human; D058112:Septins; D020123:Sirolimus
Anti-apoptosis; Anti-apoptotic; Apoptosis; Cell size; Cell survival; Programmed cell death