Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels.
Mutations in the parkin gene result in an autosomal recessive juvenile-onset form of Parkinson's disease. As an E3 ubiquitin-ligase, parkin promotes the attachment of ubiquitin onto specific substrate proteins. Defects in the ubiquitination of parkin substrates are therefore believed to lead to neurodegeneration in Parkinson's disease. Here, we identify the PSD-95/Discs-large/Zona Occludens-1 (PDZ) protein PICK1 as a novel parkin substrate. We find that parkin binds PICK1 via a PDZ-mediated interaction, which predominantly promotes PICK1 monoubiquitination rather than polyubiquitination. Consistent with monoubiquitination and recent work implicating parkin in proteasome-independent pathways, parkin does not promote PICK1 degradation. However, parkin regulates the effects of PICK1 on one of its other PDZ partners, the acid-sensing ion channel (ASIC). Overexpression of wild-type, but not PDZ binding- or E3 ubiquitin-ligase-defective parkin abolishes the previously described, protein kinase C-induced, PICK1-dependent potentiation of ASIC2a currents in non-neuronal cells. Conversely, the loss of parkin in hippocampal neurons from parkin knockout mice unmasks prominent potentiation of native ASIC currents, which is normally suppressed by endogenous parkin in wild-type neurons. Given that ASIC channels contribute to excitotoxicity, our work provides a mechanism explaining how defects in parkin-mediated PICK1 monoubiquitination could enhance ASIC activity and thereby promote neurodegeneration in Parkinson's disease.
Joch
Monica
M
Centre for Neuronal Survival and Cell Biology of Excitable Tissues, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
Ase
Ariel R
AR
Chen
Carol X-Q
CX
MacDonald
Penny A
PA
Kontogiannea
Maria
M
Corera
Amadou T
AT
Brice
Alexis
A
Séguéla
Philippe
P
Fon
Edward A
EA
D062565:Acid Sensing Ion Channels; D000596:Amino Acids; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D015640:Ion Channel Gating; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D062565:Acid Sensing Ion Channels; D000596:Amino Acids; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; D015222:Sodium Channels; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex