Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization

Daniella Brasacchio, Amber E Alsop, Tahereh Noori, Mariam Lufti, Sweta Iyer, Kaylene J Simpson, Phillip I Bird, Ruth M Kluck, Ricky W Johnstone, Joseph A Trapani

Research output: Contribution to journalArticleResearchpeer-review

Abstract

PCAF and ADA3 associate within the same macromolecular complexes to control the transcription of many genes, including some that regulate apoptosis. Here we show that PCAF and ADA3 regulate the expression of PACS1, whose protein product is a key component of the machinery that sorts proteins among the trans-Golgi network and the endosomal compartment. We describe a novel role for PACS1 as a regulator of the intrinsic pathway of apoptosis and mitochondrial outer membrane permeabilization. Cells with decreased PACS1 expression were refractory to cell death mediated by a variety of stimuli that operate through the mitochondrial pathway, including human granzyme B, staurosporine, ultraviolet radiation and etoposide, but remained sensitive to TRAIL receptor ligation. The mitochondria of protected cells failed to release cytochrome c as a result of perturbed oligomerization of BAX and BAK. We conclude that PCAF and ADA3 transcriptionally regulate PACS1 and that PACS1 is a key regulator of BAX/BAK oligomerization and the intrinsic (mitochondrial) pathway to apoptosis.

Original languageEnglish
Pages (from-to)961-970
Number of pages10
JournalCell Death and Differentiation
Volume24
DOIs
Publication statusPublished - 2017

Cite this

Brasacchio, Daniella ; Alsop, Amber E ; Noori, Tahereh ; Lufti, Mariam ; Iyer, Sweta ; Simpson, Kaylene J ; Bird, Phillip I ; Kluck, Ruth M ; Johnstone, Ricky W ; Trapani, Joseph A. / Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. In: Cell Death and Differentiation. 2017 ; Vol. 24. pp. 961-970.
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abstract = "PCAF and ADA3 associate within the same macromolecular complexes to control the transcription of many genes, including some that regulate apoptosis. Here we show that PCAF and ADA3 regulate the expression of PACS1, whose protein product is a key component of the machinery that sorts proteins among the trans-Golgi network and the endosomal compartment. We describe a novel role for PACS1 as a regulator of the intrinsic pathway of apoptosis and mitochondrial outer membrane permeabilization. Cells with decreased PACS1 expression were refractory to cell death mediated by a variety of stimuli that operate through the mitochondrial pathway, including human granzyme B, staurosporine, ultraviolet radiation and etoposide, but remained sensitive to TRAIL receptor ligation. The mitochondria of protected cells failed to release cytochrome c as a result of perturbed oligomerization of BAX and BAK. We conclude that PCAF and ADA3 transcriptionally regulate PACS1 and that PACS1 is a key regulator of BAX/BAK oligomerization and the intrinsic (mitochondrial) pathway to apoptosis.",
author = "Daniella Brasacchio and Alsop, {Amber E} and Tahereh Noori and Mariam Lufti and Sweta Iyer and Simpson, {Kaylene J} and Bird, {Phillip I} and Kluck, {Ruth M} and Johnstone, {Ricky W} and Trapani, {Joseph A}",
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Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. / Brasacchio, Daniella; Alsop, Amber E; Noori, Tahereh; Lufti, Mariam; Iyer, Sweta; Simpson, Kaylene J; Bird, Phillip I; Kluck, Ruth M; Johnstone, Ricky W; Trapani, Joseph A.

In: Cell Death and Differentiation, Vol. 24, 2017, p. 961-970.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Brasacchio, Daniella

AU - Alsop, Amber E

AU - Noori, Tahereh

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AU - Iyer, Sweta

AU - Simpson, Kaylene J

AU - Bird, Phillip I

AU - Kluck, Ruth M

AU - Johnstone, Ricky W

AU - Trapani, Joseph A

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AB - PCAF and ADA3 associate within the same macromolecular complexes to control the transcription of many genes, including some that regulate apoptosis. Here we show that PCAF and ADA3 regulate the expression of PACS1, whose protein product is a key component of the machinery that sorts proteins among the trans-Golgi network and the endosomal compartment. We describe a novel role for PACS1 as a regulator of the intrinsic pathway of apoptosis and mitochondrial outer membrane permeabilization. Cells with decreased PACS1 expression were refractory to cell death mediated by a variety of stimuli that operate through the mitochondrial pathway, including human granzyme B, staurosporine, ultraviolet radiation and etoposide, but remained sensitive to TRAIL receptor ligation. The mitochondria of protected cells failed to release cytochrome c as a result of perturbed oligomerization of BAX and BAK. We conclude that PCAF and ADA3 transcriptionally regulate PACS1 and that PACS1 is a key regulator of BAX/BAK oligomerization and the intrinsic (mitochondrial) pathway to apoptosis.

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