Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion

Lisa M. Lindqvist, Daniel Frank, Kate McArthur, Toby A. Dite, Michael Lazarou, Jonathan S. Oakhill, Benjamin T. Kile, David L. Vaux

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5′ AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak-triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak-mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-β (IFN-β) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis.

Original languageEnglish
Pages (from-to)782-794
Number of pages13
JournalCell Death and Differentiation
Volume25
DOIs
Publication statusPublished - 11 Dec 2017

Keywords

  • inflammation
  • macroautophagy

Cite this

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title = "Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion",
abstract = "Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5′ AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak-triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak-mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-β (IFN-β) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis.",
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author = "Lindqvist, {Lisa M.} and Daniel Frank and Kate McArthur and Dite, {Toby A.} and Michael Lazarou and Oakhill, {Jonathan S.} and Kile, {Benjamin T.} and Vaux, {David L.}",
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Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion. / Lindqvist, Lisa M.; Frank, Daniel; McArthur, Kate; Dite, Toby A.; Lazarou, Michael; Oakhill, Jonathan S.; Kile, Benjamin T.; Vaux, David L.

In: Cell Death and Differentiation, Vol. 25, 11.12.2017, p. 782-794.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion

AU - Lindqvist, Lisa M.

AU - Frank, Daniel

AU - McArthur, Kate

AU - Dite, Toby A.

AU - Lazarou, Michael

AU - Oakhill, Jonathan S.

AU - Kile, Benjamin T.

AU - Vaux, David L.

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N2 - Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5′ AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak-triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak-mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-β (IFN-β) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis.

AB - Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5′ AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak-triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak-mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-β (IFN-β) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis.

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