RGD Reference Report - Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. - Rat Genome Database

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Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection.

Authors: Thompson, S  Pearson, AN  Ashley, MD  Jessick, V  Murphy, BM  Gafken, P  Henshall, DC  Morris, KT  Simon, RP  Meller, R 
Citation: Thompson S, etal., J Biol Chem. 2011 Jun 3;286(22):19331-9. doi: 10.1074/jbc.M110.197707. Epub 2011 Apr 8.
RGD ID: 8554586
Pubmed: PMID:21478148   (View Abstract at PubMed)
PMCID: PMC3103311   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M110.197707   (Journal Full-text)

We have previously shown that the cell death-promoting protein Bcl-2-interacting mediator of cell death (Bim) is ubiquitinated and degraded following a neuroprotection-conferring episode of brief ischemia (preconditioning). Here, we identify the E3 ligase that ubiquitinates Bim in this model, using a proteomics approach. Using phosphorylated GST-Bim as bait, we precipitated and identified by mass spectrometry tripartite motif protein 2 (TRIM2), a RING (really interesting new gene) domain-containing protein. The reaction between TRIM2 and Bim was confirmed using co-immunoprecipitation followed by immunoblotting. We show that TRIM2 binds to Bim when it is phosphorylated by p42/p44 MAPK but does not interact with a nonphosphorylatable Bim mutant (3ABim). 12-O-tetradecanoylphorbol-13-acetate activation of p42/p44 MAPK drives Bim ubiquitination in mouse embryonic fibroblast cells and is associated with an increased interaction between TRIM2 and Bim. One hour following preconditioning ischemia, the binding of Bim to TRIM2 increased, consistent with the time window of enhanced Bim degradation. Blocking p42/p44 MAPK activation following preconditioning ischemia with U0126 or using the nonphosphorylatable 3ABim reduced the binding between Bim and TRIM2. Immunodepletion of TRIM2 from cell lysates prepared from preconditioned cells reduced Bim ubiquitination. Finally, suppression of TRIM2 expression, using lentivirus transduction of shRNAmir, stabilized Bim protein levels and blocked neuroprotection observed in rapid ischemic tolerance. Taken together, these data support a role for TRIM2 in mediating the p42/p44 MAPK-dependent ubiquitination of Bim in rapid ischemic tolerance.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of neuron apoptotic process involved_inIMP 8554586PMID:21478148UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:Q9C0408554586PMID:21478148UniProt 
protein binding enablesIPIUniProtKB:O549188554586; 8554586; 8554586PMID:21478148UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Bcl2l11  (Bcl2-like 11)
Dynll1  (dynein light chain LC8-type 1)
Trim2  (tripartite motif-containing 2)
Ywhaz  (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta)


Additional Information