The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A)

Du, Haijuan; Huang, Yongzhao; Zaghlula, Manar; Walters, Erica; Cox, Timothy C.; Massiah, Michael A.

doi:10.1074/jbc.m113.481093

Cited by 30 publications

(68 citation statements)

References 47 publications

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“…As noted, we recently demonstrated that MID1 catalyzed the polyubiquitination of alpha4, leading to its proteasome-mediated degradation [1]. The polyubiquitination was dependent on the interaction of the Bbox1 domain and alpha4.…”

Section: Resultsmentioning

confidence: 62%

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MID1 Catalyzes the Ubiquitination of Protein Phosphatase 2A and Mutations within Its Bbox1 Domain Disrupt Polyubiquitination of Alpha4 but Not of PP2Ac

Didoronkute

et al. 2014

PLoS ONE

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MID1 is a microtubule-associated protein that belongs to the TRIM family. MID1 functions as an ubiquitin E3 ligase, and recently was shown to catalyze the polyubiquitination of, alpha4, a protein regulator of protein phosphatase 2A (PP2A). It has been hypothesized that MID1 regulates PP2A, requiring the intermediary interaction with alpha4. Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced. Using the MID1 RING-Bbox1-Bbox2 (RB1B2) construct containing the E3 ligase domains, we investigate the functional effects of mutations within the Bbox domains that are identified in patients with X-linked Opitz G syndrome (XLOS). The RB1B2 proteins harboring the C142S, C145T, A130V/T mutations within the Bbox1 domain and C195F mutation within the Bbox2 domain maintain auto-polyubiquitination activity. Qualitatively, the RB1B2 proteins containing these mutations are able to catalyze the ubiquitination of PP2Ac. In contrast, the RB1B2 proteins with mutations within the Bbox1 domain are unable to catalyze the polyubiquitination of alpha4. These results suggest that unregulated alpha4 may be the direct consequence of these natural mutations in the Bbox1 domain of MID1, and hence alpha4 could play a greater role to account for the increased amount of PP2A observed in XLOS-derived fibroblasts.

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Section: Resultsmentioning

confidence: 62%

“…The RB1B2 protein and the various mutants were purified as previously described [1], [2]. Briefly, harvested cells were stored at −80°C before being resuspended in buffer 50 mM Tris, 200 mM NaCl (pH 7.5), with protease inhibitors and lysed with sarkosyl and sonication.…”

Section: Methodsmentioning

confidence: 99%

MID1 Catalyzes the Ubiquitination of Protein Phosphatase 2A and Mutations within Its Bbox1 Domain Disrupt Polyubiquitination of Alpha4 but Not of PP2Ac

Didoronkute

et al. 2014

PLoS ONE

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“…Mid1 has been established as showing female bias and escaping X-inactivation (Dal Zotto et al, 1998; Yang et al, 2010). Mid1 protein associates with the microtubules and acts as an E3 ubiquitin ligase that regulates phosphatase 2A degradation (Collison et al, 2013; Du et al, 2013; Trockenbacher et al, 2001). Mid1 -nu ll mice show hypoplasia of the vermis, the anterior portion of the medial cerebellum, correlating with impairments in motor coordination and learning (Lancioni et al, 2010); this suggests that Mid1 is important for normal development of the cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus

et al. 2014

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The cerebral cortex and hippocampus are important for the control of cognitive functions and social behaviors, many of which are sexually dimorphic and tightly regulated by gonadal steroid hormones via activation of their respective nuclear receptors. As different levels of sex steroid hormones are present between the sexes during early development and their receptors act as transcription factors to regulate gene expression, we hypothesize that sexually dimorphic gene expression in the developing mouse cortex and hippocampus might result in sex differences in brain structures and neural circuits governing distinct behaviors between the sexes as adults. To test our hypothesis, we used gene expression microarrays to identify 90 candidate genes differentially expressed in the neonatal cortex/hippocampus between male and female mice, including 55 male-biased and 35 female-biased genes. Among these genes, sexually dimorphic expression of eight sex chromosome genes was confirmed by reverse transcription with quantitative PCR (RT-qPCR), including three located on the X chromosome (Xist, Eif2s3x, and Kdm6a), three on the Y chromosome (Ddx3y, Eif2s3y, and Kdm5d), and two in the pseudoautosomal region of the X and Y chromosomes (Erdr1 and Mid1). In addition, five autosomal genes (Cd151, Dab2, Klk8, Meg3, and Prkdc) were also validated for their sexually dimorphic expression in the neonatal mouse cortex/hippocampus. Gene Ontology annotation analysis suggests that many of these sexually dimorphic genes are involved in histone modifications, cell proliferation/death, androgen/estrogen signaling pathways, and synaptic organization, and these biological processes have been implicated in differential neural development, cognitive function, and neurological diseases between the sexes.

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“…The XLID protein MID1, a microtubule-associated ubiquitin E3 ligase, facilitates MID1-dependent regulation of protein phosphatase 2A (PP2A). It has recently been shown to catalyze the polyubiquitination of alpha 4 (α4), a key regulator of PP2A and mTOR (Du et al, 2013). Mutations in another E3 ubiquitn ligase, HUWE1, have been found in patients with ID (Froyen et al, 2008).…”

Section: Genes Linked To Id and Asdmentioning

confidence: 99%

Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms

Srivastava

Schwartz

2014

Neuroscience & Biobehavioral Reviews

189

153

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Intellectual disability (ID) and Autism Spectrum disorder (ASD) are the most common developmental disorders present in humans. Combined, they affect between 3-5% of the population. Additionally, they can be found together in the same individual thereby complicating treatment. The causative factors (genes, epigenetic and environmental) are quite varied and likely interact so as to further complicate the assessment of an individual patient. Nonetheless, much valuable information has been gained by identifying candidate genes for ID or ASD. Understanding the etiology of either ID or ASD is of utmost importance for families. It allows a determination of the risk of recurrence, the possibility of other comorbidity medical problems, the molecular and cellular nature of the pathobiology and hopefully potential therapeutic approaches.

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The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A)

Cited by 30 publications

References 47 publications

MID1 Catalyzes the Ubiquitination of Protein Phosphatase 2A and Mutations within Its Bbox1 Domain Disrupt Polyubiquitination of Alpha4 but Not of PP2Ac

MID1 Catalyzes the Ubiquitination of Protein Phosphatase 2A and Mutations within Its Bbox1 Domain Disrupt Polyubiquitination of Alpha4 but Not of PP2Ac

Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus

Intellectual disability and autism spectrum disorders: Causal genes and molecular mechanisms

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