The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells

Vivian Gama, Vijay Swahari, Johanna Schafer, Adam J. Kole, Allyson Evans, Yolanda Huang, Anna Cliffe, Brian Golitz, Noah Sciaky, Xin Hai Pei, Yue Xiong, Mohanish Deshmukh

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The ability to withstand mitochondrial damage is especially critical for the survival of postmitotic cells, such as neurons. Likewise, cancer cells can also survivemitochondrial stress.We found that cytochrome c (Cyt c), which induces apoptosis upon its release from damaged mitochondria, is targeted for proteasome-mediated degradation in mouse neurons, cardiomyocytes, and myotubes and in human glioma and neuroblastoma cells, but not in proliferating human fibroblasts. In mouse neurons, apoptotic protease-activating factor 1 (Apaf-1) prevented the proteasome-dependent degradation of Cyt c in response to induced mitochondrial stress. An RNA interference screen in U-87 MG glioma cells identified p53-associated Parkin-like cytoplasmic protein (PARC, also known as CUL9) as an E3 ligase that targets Cyt c for degradation. The abundance of PARC positively correlated with differentiation in mouse neurons, and overexpression of PARC reduced the abundance of mitochondrially-released cytosolic Cyt c in various cancer cell lines and in mouse embryonic fibroblasts. Conversely, neurons from Parc-deficientmice had increased sensitivity to mitochondrial damage, and neuroblastoma or glioma cells in which PARC or ubiquitin was knocked down had increased abundance of mitochondrially-released cytosolic Cyt c and decreased viability in response to stress. These findings suggest that PARC-mediated ubiquitination and degradation of Cyt c is a strategy engaged by both neurons and cancer cells to prevent apoptosis during conditions of mitochondrial stress.

Original languageEnglish (US)
Article numberra67
JournalScience Signaling
Issue number334
DOIs
StatePublished - Jul 15 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Gama, V., Swahari, V., Schafer, J., Kole, A. J., Evans, A., Huang, Y., Cliffe, A., Golitz, B., Sciaky, N., Pei, X. H., Xiong, Y., & Deshmukh, M. (2014). The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. Science Signaling, (334), [ra67]. https://doi.org/10.1126/scisignal.2005309