title: The Proapoptotic F-box Protein Fbxl7 Regulates Mitochondrial Function by Mediating the Ubiquitylation and Proteasomal Degradation of Survivin.
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.
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and.
authors.forename: Travis
authors.initials: T
authors.lastname: Lear
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and.
authors.forename: Olivia
authors.initials: O
authors.lastname: Iannone
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corey
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and.
authors.forename: Shristi
authors.initials: S
authors.lastname: Rajbhandari
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and.
authors.forename: Jacob
authors.initials: J
authors.lastname: Jerome
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and chenb@upmc.edu.
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.affiliation: From the Department of Medicine, Acute Lung Injury Center of Excellence and the Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240 mallampallirk@upmc.edu.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D004734:Energy Metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017433:Protein Structure, Secondary; D012097:Repressor Proteins / Q000378:metabolism; D000077022:Survivin; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000255:Adenosine Triphosphate; D044783:F-Box Proteins; D051034:Inhibitor of Apoptosis Proteins; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins; D000077022:Survivin; D025801:Ubiquitin; C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; C529982:FBXL7 protein, human; C000599899:Fbxl7 protein, mouse
keywords: Cell Biology; E3 Ubiquitin Ligase; Lung Injury; Mitochondria; Oxygen; Protein Degradation