Article Figures & Data
Figures
- Figure 1.
Neuronal ubiquitination and ubiquitin-like modifications. A, C, Major components of excitatory and inhibitory synapses targeted by ubiquitin (blue squares) SUMO (purple triangles) and NEDD8 (orange hexagons) pathways. Deubiquitinating enzymes (green clamshell-like shapes) and components of the SUMO (UBC9 and SENPs) and NEDD8 machineries (NAE, UBC12, and UBE2F) are also indicated. Although NEDD8 pathway and targets are also present in the presynaptic compartment, for simplicity they are depicted in the postsynaptic region only. In A, E3 ubiquitin ligases operating at excitatory synapses and their known substrates are listed in the left table. B, Nuclear sumoylation and neddylation critical to synaptic function are indicated.
- Figure 2.
Postsynaptic control of glutamate and GABAA receptors by ubiquitination and sumoylation. UPS-dependent degradation (green arrows) of PSD-95 destabilizes surface AMPARs, resulting in enhanced receptor lateral mobility and consequently, endocytosis (box A). Ubiquitination of GluA1 and GluA2 decreases surface AMPARs through clathrin-dependent endocytosis (orange arrows). Ubiquitinated ARC is degraded via the UPS pathway. As ARC is a major regulator of AMPAR internalization, reduced ARC levels suppress AMPAR endocytosis. Conversely, sumoylated ARC triggers AMPAR internalization. Moreover, ubiquitination of intracellular GluA1-4 may also promote AMPAR sorting to the lysosomal degradation pathway (red arrows). Ubiquitination of mGlu1-5 receptors enhanced their clathrin-dependent endocytosis. Surface NMDARs are regulated by the ubiquitination pathway in a subunit-dependent manner. GluN2B undergoes a phosphorylation-dependent ubiquitination (box B), leading to UPS-dependent degradation of NMDARs. GluN2D ubiquitination enhances its degradation, although it is not clear whether it utilizes UPS-dependent or lysosomal-dependent pathways (green and red dotted arrows). Finally, ubiquitination of newly synthetized GluN1 and GluN2A results in NMDAR retrotranslocation from the ER to the cytosol and subsequent degradation through the ERAD pathway (blue arrows). Similar to GluN2D, GluK2 ubiquitination is phosphorylation-dependent and triggers its degradation through an as yet ill-defined pathway (green and red dotted arrows). In contrast, sumoylated GluK2-containing KARs are removed from the synaptic membrane via clathrin-dependent endocytosis. At inhibitory synapses, ubiquitinated γ2-containing GABAAR are sorted to the lysosomal degradation pathway, while β3-containing GABAAR are ubiquitinated in the ER and degraded through the ERAD machinery.
Tables
- Table 1
Rare monogenic forms of ID linked to mutations of components or regulators of the ubiquitin pathway
Gene Protein Disease Genetic abnormalities References ASXL3 Component of the Polycomb repressive deubiquitination (PR-DUB) complex Bainbridge–Ropers syndrome, BRS (OMIM 615485) and ASD De novo truncating mutations in BRS and missense mutations in ASD Bainbridge et al. (2013); De Rubeis et al. (2014) CUL4B Scaffolding protein stabilizing cullin RING E3 ligase XLID (OMIM 300304) Missense mutations Wang et al. (2013); Zou et al. (2007) HECW2 E3 ubiquitin ligase HECW2 Neurodevelopmental disorder with hypotonia, seizures, and absent language, NDHSAL (OMIM 617268) Missense mutations Halvardson et al. (2016) HERC1 E3 ubiquitin ligase HERC1 Macrocephaly, dysmorphic facies, and psychomotor retardation, MDFPMR (OMIM 617011) Missense and frameshift mutations Aggarwal et al. (2016); Nguyen et al. (2016); Ortega-Recalde et al. (2015) HERC2 E3 ubiquitin ligase HERC2 Syndrome of ID, autism, and variable neurological deficits (OMIM 615516) Missense mutations Puffenberger et al. (2012) HUWE1 HECT, UBA, and WWE domain containing 1, E3 ubiquitin protein ligase Turner type, XLID
(OMIM 309590)Microduplications, missense mutations Froyen et al. (2008); Moortgat et al. (2018) MAGEL2 E3 ubiquitin ligase enhancer Prader–Willi syndrome, PWS (OMIM 176270) and Schaaf–Yang syndrome, SHFYNG (OMIM 615547) Interstitial deletions and maternal uniparental disomy in PWS; truncating mutations in SHFYNG Tacer and Potts (2017) MID2 Member of the TRIpartite motif (TRIM) family of RING E3 ligases XLID (OMIM 300928) Missense mutation Geetha et al. (2014) OTUD6B Member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, IDDFSDA (OMIM 617452) Truncating and missense mutations Santiago-Sim et al. (2017) PLAA Ubiquitin binding protein phospholipase A2 activating protein Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, NDMSBA (OMIM 617527) Missense mutations Falik Zaccai et al. (2017); Hall et al. (2017) RLIM RNF12 E3 ubiquitin ligase Tonne–Kalscheuer syndrome, XLID (OMIM 300978) Missense mutation Tønne et al. (2015) TRIM50 Member of the TRIpartite motif (TRIM) family of RING E3 ligases William–Beuren syndrome, WBS (OMIM 194050) Microdeletion on chr. 7q11.23 Micale et al. (2008) TRIP12 Member of the HECT domain E3 ubiquitin ligases family ID with or without ASD (OMIM 6177520) CNVs, missense, frameshift, splicing mutations Zhang et al. (2017) UBE2A E2 ubiquitin conjugating enzyme E2A XLID type Nascimento
(OMIM 300860)Truncating and missense mutations Budny et al. (2010); Nascimento et al. (2006) UBE3B E3 ubiquitin ligase E3B Blepharophimosis-ptosis-ID syndrome, BPIDS (OMIM 244450) Truncating mutations Basel-Vanagaite et al. (2012) USPX9 Deubiquitinating enzyme FAF-X Female-restricted X-linked non-syndromic mental retardation-99 (OMIM 300919) Truncating mutation and X-chr. deletion Au et al. (2017) XLID: X-linked ID, CNV: copy number variation.
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