RGD Reference Report - Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway. - Rat Genome Database

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Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway.

Authors: Salinas, GD  Blair, LA  Needleman, LA  Gonzales, JD  Chen, Y  Li, M  Singer, JD  Marshall, J 
Citation: Salinas GD, etal., J Biol Chem. 2006 Dec 29;281(52):40164-73. Epub 2006 Oct 24.
RGD ID: 8553595
Pubmed: PMID:17062563   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M608194200   (Journal Full-text)

Kainate receptors have been implicated in excitotoxic neuronal death induced by diseases such as epilepsy and stroke. Actinfilin, a synaptic member of the BTB-Kelch protein family, is known to bind to the actin cytoskeleton. However, little is understood about its function at the synapse. Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. We map this interaction to the Kelch repeat domain of actinfilin and the GluR6 C terminus. Co-immunoprecipitation and immunofluorescence studies show that GluR6 is ubiquitinated, and that GluR6 levels are decreased by actinfilin overexpression but increased when actinfilin levels are reduced by specific RNA interference. Furthermore, actinfilin-Cul3 interactions appear to be important for regulating surface GluR6 expression. Synaptic GluR6 levels are elevated in mice with lowered neuronal Cul3 expression and when dominant-negative forms of Cul3 are transfected into hippocampal neurons. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation protein catabolic process at postsynapse involved_inIDA 8553595PMID:17062563SynGO 
regulation protein catabolic process at postsynapse involved_inIMP 8553595PMID:17062563SynGO 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
glutamatergic synapse is_active_inIDA 8553595PMID:17062563SynGO 
glutamatergic synapse is_active_inIMP 8553595PMID:17062563SynGO 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Cul3  (cullin 3)
Grik1  (glutamate ionotropic receptor kainate type subunit 1)
Grik2  (glutamate ionotropic receptor kainate type subunit 2)
Klhl17  (kelch-like family member 17)


Additional Information