PMID:22072718

Citation	Niture, SK and Jaiswal, AK (2011) Inhibitor of Nrf2 (INrf2 or Keap1) protein degrades Bcl-xL via phosphoglycerate mutase 5 and controls cellular apoptosis. J. Biol. Chem. 286:44542-56
Abstract	INrf2 (Keap1) is an adaptor protein that facilitates INrf2-Cul3-Rbx1-mediated ubiquitination/degradation of Nrf2, a master regulator of cytoprotective gene expression. Here, we present evidence that members of the phosphoglycerate mutase family 5 (PGAM5) proteins are involved in the INrf2-mediated ubiquitination/degradation of anti-apoptotic factor Bcl-xL. Mass spectrometry and co-immunoprecipitation assays revealed that INrf2, through its DGR domain, interacts with PGAM5, which in turn interacts with anti-apoptotic Bcl-xL protein. INrf2-Cul3-Rbx1 complex facilitates ubiquitination and degradation of both PGAM5 and Bcl-xL. Overexpression of PGAM5 protein increased INrf2-mediated degradation of Bcl-xL, whereas knocking down PGAM5 by siRNA decreased INrf2 degradation of Bcl-xL, resulting in increased stability of Bcl-xL. Mutation of PGMA5-E79A/S80A abolished INrf2/PGAM5/Bcl-xL interaction. Therefore, PGAM5 protein acts as a bridge between INrf2 and Bcl-xL interaction. Further studies showed that overexpression of INrf2 enhanced degradation of PGAM5-Bcl-xL complex, led to etoposide-mediated accumulation of Bax, increased release of cytochrome c from mitochondria, activated caspase-3/7, and enhanced DNA fragmentation and apoptosis. In addition, antioxidant (tert-butylhydroquinone) treatment destabilized the Nrf2-INrf2-PGAM5-Bcl-xL complex, which resulted in release of Nrf2 in cytosol and mitochondria, release of Bcl-xL in mitochondria, increase in Bcl-xL heterodimerization with Bax in mitochondria, and reduced cellular apoptosis. These data provide the first evidence that INrf2 controls Bcl-xL via PGAM5 and controls cellular apoptosis.
Links	PubMed PMC3247995 Online version:10.1074/jbc.M111.275073
Keywords	Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Amino Acid Substitution; Animals; Apoptosis/physiology; Carrier Proteins/genetics; Carrier Proteins/metabolism; Caspase 3/genetics; Caspase 3/metabolism; Caspase 7/genetics; Caspase 7/metabolism; Cell Line, Tumor; Cullin Proteins/genetics; Cullin Proteins/metabolism; Cytochromes c/genetics; Cytochromes c/metabolism; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Cytosol/metabolism; DNA Fragmentation; Mice; Mitochondria/genetics; Mitochondria/metabolism; Multiprotein Complexes/genetics; Multiprotein Complexes/metabolism; Mutation, Missense; Phosphoglycerate Mutase/genetics; Phosphoglycerate Mutase/metabolism; Phosphoric Monoester Hydrolases/genetics; Phosphoric Monoester Hydrolases/metabolism; Protein Stability; Protein Structure, Tertiary; Proteolysis; Ubiquitination/physiology; bcl-X Protein/genetics; bcl-X Protein/metabolism
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Significance

Note: this paper has been retracted.

http://www.ncbi.nlm.nih.gov/pubmed/25108015

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:NF2L2		GO:0005739: mitochondrion	ECO:0000314:		C		Fig. 6A	complete CACAO 3006
MOUSE:NF2L2		GO:0043066: negative regulation of apoptosis	ECO:0000315:		P		Fig. 9CD	complete CACAO 3007
HUMAN:KEAP1		GO:0030972: cleavage of cytosolic proteins involved in apoptosis	ECO:0000315:		P		Fig. 8D	complete CACAO 3012
HUMAN:KEAP1		GO:0045732: positive regulation of protein catabolic process	ECO:0000315:		P		Fig. 1 and Fig. 8A	complete CACAO 3016
HUMAN:KEAP1		GO:0032270: positive regulation of cellular protein metabolic process	ECO:0000315:		P		Fig. 8A	complete CACAO 3030
HUMAN:KEAP1		GO:0016567: protein ubiquitination	ECO:0000315:		P		Fig. 3A	complete CACAO 3031
MOUSE:KEAP1		GO:0005739: mitochondrion	ECO:0000314:		C		Fig. 6A	complete CACAO 3017
MOUSE:KEAP1		GO:0030972: cleavage of cytosolic proteins involved in apoptosis	ECO:0000314:		P		Fig. 8D	complete CACAO 3020
MOUSE:KEAP1		GO:0043280: positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	ECO:0000314:		P		Fig. 8C	complete CACAO 3021
MOUSE:KEAP1		GO:0001836: release of cytochrome c from mitochondria	ECO:0000314:		P		Fig. 8B	complete CACAO 3022
MOUSE:KEAP1		GO:0016567: protein ubiquitination	ECO:0000314:		P		Fig. 3BC	complete CACAO 3024
MOUSE:KEAP1		GO:0045732: positive regulation of protein catabolic process	ECO:0000314:		P		Fig. 1 and Fig. 8A	complete CACAO 3025
MOUSE:PGAM5		GO:0005739: mitochondrion	ECO:0000314:		C		Fig. 6A	complete CACAO 3003
MOUSE:PGAM5		GO:0043065: positive regulation of apoptosis	ECO:0000315:		P		Fig. 9B	complete CACAO 3004
MOUSE:PGAM5		GO:0070585: protein localization in mitochondrion	ECO:0000315:		P		Fig. 6B	complete CACAO 3005
MOUSE:BAD		GO:0005739: mitochondrion	ECO:0000314:		C		Fig. 6A	complete CACAO 3002

References

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