Autophagy occurs upstream or parallel to the apoptosome during histolytic cell death.
Histolysis refers to a widespread disintegration of tissues that is morphologically distinct from apoptosis and often associated with the stimulation of autophagy. Here, we establish that a component of the apoptosome, and pivotal regulator of apoptosis, is also required for histolytic cell death. Using in vivo and ex vivo assays, we demonstrate a global apoptogenic requirement for dark, the fly ortholog of Apaf1, and show that a required focus of dark(-) organismal lethality maps to the central nervous system. We further demonstrate that the Dark protein itself is a caspase substrate and find that alterations of this cleavage site produced the first hypermorphic point mutation within the Apaf1/Ced-4 gene family. In a model of ;autophagic cell death', dark was essential for histolysis but dispensable for characteristic features of the autophagic program, indicating that the induction of autophagy occurs upstream or parallel to histolytic cell death. These results demonstrate that stimulation of autophagy per se is not a ;killing event' and, at the same time, establish that common effector pathways, regulated by the apoptosome, can underlie morphologically distinct forms of programmed cell death.
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Fatih
F
Akdemir
Robert
R
Farkas
Po
P
Chen
Gabor
G
Juhasz
Lucia
L
Medved'ová
Miklos
M
Sass
Lai
L
Wang
Xiaodong
X
Wang
Suganthi
S
Chittaranjan
Sharon M
SM
Gorski
Antony
A
Rodriguez
John M
JM
Abrams
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002490:Central Nervous System / Q000502:physiology; D004330:Drosophila / Q000166:cytology* / Q000235:genetics / Q000254:growth & development*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D007814:Larva / Q000235:genetics / Q000254:growth & development; D016296:Mutagenesis; D009928:Organ Specificity / Q000235:genetics; D012469:Salivary Glands / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D019076:Transgenes; D015053:Zygote / Q000502:physiology
D029721:Drosophila Proteins; C400550:dark protein, Drosophila