Pro-apoptotic F-box protein Fbxl7 regulates mitochondrial function by mediating the ubiquitylation and proteasomal degradation of survivin [Bioenergetics]

March 16th, 2015 by Liu, Y., Lear, T., Iannone, O., Shiva, S., Corey, C., Rajbhandari, S., Jerome, J., Chen, B. B., Mallampalli, R. K.

Fbxl7, a component of the SCF (Skp1-Cul1-F-box protein) type ubiquitin E3 ligase, regulates mitotic cell cycle progression. Here, we demonstrate that overexpression of Fbxl7 in lung epithelia decreases protein abundance of survivin, a member of the inhibitor of apoptosis (IAP) family. Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with E126 within its carboxyl-terminal alpha-helix. Further, both K90 and K91 within survivin serve as ubiquitin acceptors sites. Ectopically expressed Fbxl7 impairs mitochondrial function, whereas depletion of Fbxl7 protects mitochondria from actions of carbonyl cyanide m-chlorophenyl hydrazone (CCCP), an inhibitor of oxidative phosphorylation. Compared to wild type survivin, cellular expression of a survivin mutant protein deficient in its ability to interact with Fbxl7 (E126A), and a ubiquitylation resistant double point mutant (KK90/91RR) rescued mitochondria to a larger extent from damage induced by overexpression of Fbxl7. Thus, these data suggest that the SCF complex subunit Fbxl7 modulates mitochondrial function by controlling cellular abundance of survivin. The results raise opportunities for F box protein targeting to preserve mitochondrial function.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Pro-apoptotic F-box protein Fbxl7 regulates mitochondrial function by mediating the ubiquitylation and proteasomal degradation of survivin [Bioenergetics]