Abstract
The Activation-Induced Cell Death (AICD) is a stimulation-dependent form of apoptosis used by the organism to shutdown T-cell response once the source of inflammation has been eliminated, while allowing the generation of immune memory. AICD is thought to progress through the activation of the extrinsic Fas/FasL pathway of cell death, leading to cytochrome-C release through caspase-8 and Bid activation. We recently described that, early upon AICD induction, mitochondria undergo structural alterations, which are required to promote cytochrome-C release and execute cell death. Here, we found that such alterations do not depend on the Fas/FasL pathway, which is instead only lately activated to amplify the cell death cascade. Instead, such alterations are primarily dependent on the MAPK proteins JNK1 and ERK1/2, which, in turn, regulate the activity of the pro-fission protein Drp1 and the pro-apoptotic factor Bim. The latter regulates cristae disassembly and cooperate with Drp1 to mediate the Mitochondrial Outer Membrane Permeabilization (MOMP), leading to cytochrome-C release. Interestingly, we found that Bim is also downregulated in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells, this alteration favouring their escape from AICD-mediated control. © 2020, The Author(s).
Original language | English |
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Pages (from-to) | 2749-2767 |
Number of pages | 19 |
Journal | Cell Death Differ. |
Volume | 27 |
Issue number | 10 |
DOIs | |
Publication status | Published - 2020 |
Keywords
- BIM protein
- cytochrome c
- dynamin
- dynamin related protein 1
- mitogen activated protein kinase 1
- mitogen activated protein kinase 3
- stress activated protein kinase 1
- unclassified drug
- acute T-cell leukemia cell line
- adult
- animal cell
- animal experiment
- animal model
- animal tissue
- Article
- cell permeabilization
- controlled study
- down regulation
- drug targeting
- homeostasis
- human
- human cell
- lymphocyte
- male
- MAPK signaling
- mitochondrion
- mouse
- nonhuman
- outer membrane
- priority journal
- protein expression
- protein secretion
- restimulation induced cell death