The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin*
- Yuan Liu‡,
- Travis Lear‡,
- Olivia Iannone‡,
- Sruti Shiva§,
- Catherine Corey§,
- Shristi Rajbhandari‡,
- Jacob Jerome‡,
- Bill B. Chen‡12 and
- Rama K. Mallampalli‡,¶13
- From the ‡Department of Medicine, Acute Lung Injury Center of Excellence and
- §Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and
- the ¶Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240
- ↵2 To whom correspondence may be addressed: Pulmonary, Allergy, and Critical Care Medicine, Biomedical Science Tower 1, W1254, Dept. of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. Tel.: 412-624-2664; E-mail: chenb{at}upmc.edu.
- ↵3 To whom correspondence may be addressed: Pulmonary, Allergy, and Critical Care Medicine, UPMC Montefiore, NW628, Dept. of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. Tel.: 412-624-8900; Fax: 412-692-2260; E-mail: mallampallirk{at}upmc.edu.
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↵1 Both authors contributed equally to this work.
Abstract
Fbxl7, a component of the 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 the protein abundance of survivin, a member of the inhibitor of apoptosis family. Fbxl7 mediates polyubiquitylation and proteasomal degradation of survivin by interacting with Glu-126 within its carboxyl-terminal α helix. Furthermore, both Lys-90 and Lys-91 within survivin serve as ubiquitin acceptor sites. Ectopically expressed Fbxl7 impairs mitochondrial function, whereas depletion of Fbxl7 protects mitochondria from actions of carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of oxidative phosphorylation. Compared with 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 (KK90RR/KK91RR) rescued mitochondria to a larger extent from damage induced by overexpression of Fbxl7. Therefore, these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. The results raise opportunities for F-box protein targeting to preserve mitochondrial function.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health R01 Grants HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, and P01 HL114453 (to R. K. M.) and HL116472 (to B. B. C.). This work was also supported by a merit review award from the Department of Veterans Affairs and the Flight Attendants Medical Research Institute.
- Received December 2, 2014.
- Revision received March 13, 2015.
- © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
