JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction: Cell Death and Differentiation

L. Simula, M. Corrado, B. Accordi, A. Di Rita, F. Nazio, Y. Antonucci, A. Di Daniele, F. Caicci, I. Caruana, M.E. Soriano, M. Pigazzi, F. Locatelli, F. Cecconi, S. Campello

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)2749-2767
Number of pages19
JournalCell Death Differ.
Volume27
Issue number10
DOIs
Publication statusPublished - 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

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