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PMID:16252010

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Citation

Geetha, T, Kenchappa, RS, Wooten, MW and Carter, BD (2005) TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor. EMBO J. 24:3859-68

Abstract

TRAF6 is an E3 ubiquitin ligase that mediates signaling from members of the tumor necrosis factor and Toll-like receptor superfamilies, including the p75 neurotrophin receptor. Recently, TRAF6 was shown to bind to another p75 cytoplasmic interactor, NRIF, and promote its nuclear localization. Here, we demonstrate that NRIF is a substrate for TRAF6-mediated K63 polyubiquitination and that this modification is necessary for its nuclear translocation. Activation of p75 resulted in NRIF polyubiquitination, association with TRAF6 and nuclear localization. NRIF was polyubiquitinated by TRAF6 in vitro and in cultured cells, and this was abrogated by mutation of K19 in the amino-terminus of NRIF. The K19R mutant NRIF displayed reduced TRAF6 association and neurotrophin-dependent nuclear localization. In neurons from traf6-/- mice, NRIF failed to enter the nucleus in response to p75 activation, and polyubiquitination and nuclear localization were attenuated in traf6-/- brain. Finally, unlike wild-type NRIF, the K19R NRIF failed to reconstitute p75-mediated apoptosis in nrif-/- neurons. These results reveal a unique mechanism of p75 signaling and a novel role for K63-linked ubiquitin chains.

Links

PubMed PMC1283944 Online version:10.1038/sj.emboj.7600845

Keywords

Active Transport, Cell Nucleus/physiology; Animals; Apoptosis; Brain/metabolism; Cell Line; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Ligands; Lysine/metabolism; Mice; Mice, Knockout; Neurons/cytology; Neurons/metabolism; Polyubiquitin/metabolism; Protein Binding; Receptor, Nerve Growth Factor/metabolism; TNF Receptor-Associated Factor 6/genetics; TNF Receptor-Associated Factor 6/metabolism; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SQSTM

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q923B3

F

Seeded From UniProt

complete

MOUSE:NRIF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q64337

F

Seeded From UniProt

complete

MOUSE:NRIF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NRIF1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NRIF1

involved_in

GO:0051402: neuron apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRAF6

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TRAF6

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TRAF6

involved_in

GO:0070534: protein K63-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SQSTM

enables

GO:0070530: K63-linked polyubiquitin modification-dependent protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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