Ring Finger Protein 34 (RNF34) Interacts with and Promotes γ-Aminobutyric Acid Type-A Receptor Degradation via Ubiquitination of the γ2 Subunit

Jin, Hongbing; Chiou, Tzu‐Ting; Serwanski, David R.; Miralles, Celia P.; Pinal, Noelia; Blas, Angel L. De

doi:10.1074/jbc.m114.603068

Cited by 28 publications

(32 citation statements)

References 70 publications

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“…Immunofluorescence can be blocked with the antigenic peptide. This antibody is in the JCN database and it has been described and characterized elsewhere (Charych et al, ; Charych et al, ; Chiou et al, ; Christie and De Blas, ; Christie et al, ; Fekete et al, ; Jin et al, ; Li et al, , ; Yu and De Blas, ; Yu et al, ).…”

Section: Methodsmentioning

confidence: 99%

In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex

Fekete

Goz

Dinallo

et al. 2016

J of Comparative Neurology

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Collybistin (CB) is a guanine nucleotide exchange factor selectively localized to γ-aminobutyric acid (GABA)ergic and glycinergic postsynapses. Active CB interacts with gephyrin, inducing the submembranous clustering and the postsynaptic accumulation of gephyrin, which is a scaffold protein that recruits GABA receptors (GABA Rs) at the postsynapse. CB is expressed with or without a src homology 3 (SH3) domain. We have previously reported the effects on GABAergic synapses of the acute overexpression of CB or CB in cultured hippocampal (HP) neurons. In the present communication, we are studying the effects on GABAergic synapses after chronic in vivo transgenic expression of CB2 or CB2 in neurons of the adult rat cerebral cortex. The embryonic precursors of these cortical neurons were in utero electroporated with CB or CB DNAs, migrated to the appropriate cortical layer, and became integrated in cortical circuits. The results show that: 1) the strength of inhibitory synapses in vivo can be enhanced by increasing the expression of CB in neurons; and 2) there are significant differences in the results between in vivo and in culture studies. J. Comp. Neurol. 525:1291-1311, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex

Fekete

Goz

Dinallo

et al. 2016

J of Comparative Neurology

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“…The Rb antibody to the γ2 subunit of the rat GABA A R (to amino acids 1–15 QKSDDDYEDYASNKT) was raised and affinity‐purified (on immobilized antigen peptide) in our laboratory and has been described and characterized elsewhere (Christie et al, , ; Christie and De Blas, ; Charych et al, ; Li et al, ; Yu et al, ; Yu and De Blas, ; Chiou et al, ; Jin et al, ). The RRID is AB_2314477 and it is in the Journal of Comparative Neurology (JCN) antibody database.…”

Section: Methodsmentioning

confidence: 99%

“…The immunoreactivity of the protein band was displaced by antigenic peptide; 4) strong NL3 immunofluorescence signal in human embryonic kidney 293 (HEK293) cells transfected with pCAGGS-HA-NL3 compared to the very low background immunofluorescence signal of neighboring nontransfected cells or HEK293 cells transfected with pCAGGS-HA-NL1 or pCAGGS-HA-NL2; 5) neuronal transfection in culture or in vivo with pCAGGS-HA-NL3 showed colocalizing anti-NL3 and anti-HA immunofluorescence signals; 6) neuronal transfection with pCAGGS-HA-NL1 or pCAGGS-HA-NL2 showed anti-HA fluorescence but not anti-NL3 fluorescence. The Rb antibody to the g2 subunit of the rat GABA A R (to amino acids 1-15 QKSDDDYEDYASNKT) was raised and affinity-purified (on immobilized antigen peptide) in our laboratory and has been described and characterized elsewhere (Christie et al, 2002a(Christie et al, , 2002b(Christie et al, , 2006Christie and De Blas, 2003;Charych et al, 2004;Li et al, 2005Li et al, , 20072010, 2012Yu et al, 2007;Yu and De Blas, 2008;Chiou et al, 2011;Jin et al, 2014). The RRID is AB_2314477 and it is in the Journal of Comparative Neurology (JCN) antibody database.…”

Section: Antibodies and Plasmidsmentioning

confidence: 99%

In vivo clonal overexpression of neuroligin 3 and neuroligin 2 in neurons of the rat cerebral cortex: Differential effects on GABAergic synapses and neuronal migration

Fekete

Chiou

Miralles

et al. 2015

J of Comparative Neurology

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We have studied the effect of clonal overexpression of neuroligin 3 (NL3) or neuroligin 2 (NL2) in the adult rat cerebral cortex following in utero electroporation (IUEP) at embryonic stage E14. Overexpression of NL3 leads to a large increase in vGAT and GAD65 in the GABAergic contacts that the overexpressing neurons receive. Overexpression of NL2 produced a similar effect but to a lesser extent. In contrast, overexpression of NL3 or NL2 after IUEP, does not affect vGlut1 in the glutamatergic contacts that the NL3 or NL2 overexpressing neurons receive. The NL3 or NL2 overexpressing neurons do not show increased innervation by parvalbumin-containing GABAergic terminals or increased parvalbumin in the same terminals that show increased vGAT. These results indicate that the observed increase in vGAT and GAD65 is not due to increased GABAergic innervation but to increased expression of vGAT and GAD65 in the GABAergic contacts that NL3 or NL2 overexpressing neurons receive. The majority of bright vGAT puncta contacting the NL3 overexpressing neurons have no gephyrin juxtaposed to them indicating that many of these contacts are non-synaptic. This contrasts with the majority of the NL2 overexpressing neurons, which show plenty of synaptic gephyrin clusters juxtaposed to vGAT. Besides having an effect on GABAergic contacts, overexpression of NL3 interferes with the neuronal radial migration, in the cerebral cortex, of the neurons overexpressing NL3.

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“…What other E3 ligases play an important role in the ubiquitination of the ␣1 subunits? Recently, it was reported that ring finger protein 34 (RNF34) promotes the degradation of the ␥2 subunit by ubiquitinating them (67). Furthermore, our recent proteomics study identified several E3 ligases that interact with the 1 subunit, such as HUWE1 and UBR5 (68).…”

Section: Discussionmentioning

confidence: 99%

Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation

Di¹,

Wang

Han³

et al. 2016

Journal of Biological Chemistry

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Proteostasis maintenance of ␥-aminobutyric acid type A (GABA A ) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral membrane protein, even wild type subunits of GABA A receptors fold and assemble inefficiently in the endoplasmic reticulum (ER). Unassembled and misfolded subunits undergo ER-associated degradation (ERAD), but this degradation process remains poorly understood for GABA A receptors. Here, using the ␣1 subunits of GABA A receptors as a model substrate, we demonstrated that Grp94, a metazoan-specific Hsp90 in the ER lumen, uses its middle domain to interact with the ␣1 subunits and positively regulates their ERAD. OS-9, an ER-resident lectin, acts downstream of Grp94 to further recognize misfolded ␣1 subunits in a glycan-dependent manner. This delivers misfolded ␣1 subunits to the Hrd1-mediated ubiquitination and the valosin-containing protein-mediated extraction pathway. Repressing the initial ERAD recognition step by inhibiting Grp94 enhances the functional surface expression of misfolding-prone ␣1(A322D) subunits, which causes autosomal dominant juvenile myoclonic epilepsy. This study clarifies a Grp94-mediated ERAD pathway for GABA A receptors, which provides a novel way to finely tune their function in physiological and pathophysiological conditions.

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Ring Finger Protein 34 (RNF34) Interacts with and Promotes γ-Aminobutyric Acid Type-A Receptor Degradation via Ubiquitination of the γ2 Subunit

Cited by 28 publications

References 70 publications

In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex

In vivo transgenic expression of collybistin in neurons of the rat cerebral cortex

In vivo clonal overexpression of neuroligin 3 and neuroligin 2 in neurons of the rat cerebral cortex: Differential effects on GABAergic synapses and neuronal migration

Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation

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