UBE3A regulates the transcription of IRF, an antiviral immunity

Abstract

UBE3A is a gene responsible for the pathogenesis of Angelman syndrome (AS), a neurodevelopmental disorder characterized by symptoms such as intellectual disability, delayed development and severe speech impairment. UBE3A encodes an E3 ubiquitin ligase, for which several targets have been identified, including synaptic molecules. Although proteolysis mainly occurs in the cytoplasm, UBE3A is localized to the cytoplasm and the nucleus. In fact, UBE3A is also known as a transcriptional regulator of the family of nuclear receptors. However, the function of UBE3A in the nucleus remains unclear. Therefore, we examined the involvement of UBE3A in transcription in the nuclei of neurons. Genome-wide transcriptome analysis revealed an enrichment of genes downstream of interferon regulatory factor (IRF) in a UBE3A-deficient AS mouse model. In vitro biochemical analyses further demonstrated that UBE3A interacted with IRF and, more importantly, that UBE3A enhanced IRF-dependent transcription. These results suggest a function for UBE3A as a transcriptional regulator of the immune system in the brain. These findings also provide informative molecular insights into the function of UBE3A in the brain and in AS pathogenesis.

UBE3A reinstatement as a disease‐modifying therapy for Angelman syndrome

“…Moreover, multiple changes have been observed in signalling cascades that are indirectly critical to neuronal function, such as CAMK2, 35,36 Ephexin5‐EphB, 37 neuregulin‐ErbB4, 38 TrkB‐PSD‐95, 39 ERK, 40 mTORC, 41 and dopamine signalling pathways 42–45 . These widespread changes are consistent with the suggestion that UBE3A probably plays an important global regulatory role, such as transcriptional regulation and/or by regulating (nuclear) proteasome activity to which it is strongly attached 14,18,22–25 …”

“…In contrast, loss of the major nuclear isoform results in typical Angelman syndrome phenotypes in mice and humans, although in humans this is milder than in typical cases of Angelman syndrome. 12,18 Although several nuclear targets have been identified 21 and UBE3A function has directly been linked to transcription regulation, [22][23][24][25] it is not clear which nuclear targets are really critical for Angelman syndrome pathophysiology. This greatly hinders the search for UBE3A-target-based treatments.…”

“…[42][43][44][45] These widespread changes are consistent with the suggestion that UBE3A probably plays an important global regulatory role, such as transcriptional regulation and/or by regulating (nuclear) proteasome activity to which it is strongly attached. 14,18,[22][23][24][25] In the face of these widespread changes, it is rather surprising that by specifically targeting a single mechanism, an electrophysiological or even a behavioural rescue could be observed in most of the aforementioned studies. [31][32][33]36,38,39,41 It is unclear how these highly specific treatments, which reversed the behavioural phenotypes in mouse models of Angelman syndrome, can be reconciled with the notion that so many mechanisms are affected.…”

An Integrative Synthetic Biology Approach to Interrogating Cellular Ubiquitin and Ufm Signaling

“…UBE3A/E6AP was involved in many biological processes, such as Wnt signaling, circadian rhythms, imprinted gene networks, immunity responses, synapse plasticity and early brain development [ 32 , 33 ]. As UBE3A related neurodevelopmental diseases with incompletely understood mechanisms, suggesting yet undiscovered roles of UBE3A-mediated ubiquitination signal in diverse pathophysiological contexts [ 34 , 35 ]. In the YESS UB -UBE3A system, the ORF (Open reading frame) of human UBE3A was chosen and cloned into the pDEST32 to express the bait for Y2H screening, while prey library was constructed by cloning over ~20,000 human ORFs into pDEST22 vectors followed by large-scale transformation into pDEST32-UBE3A-containing yeast competent cells [ 36 ] ( Figure 1 A).…”

Lysinuric protein intolerance: Pearls to detect this otherwise easily missed diagnosis

“…Lysinuric protein intolerance (LPI; OMIM #222700) is an autosomal recessive disorder characterized by deficient membrane transport of cationic amino acids lysine, ornithine and arginine. In most cases, it is caused by pathogenic variants in SLC7A7 on chromosome 14 at locus 14q11.2 [2,21], although variants cannot be identified in this gene in 5-8% of cases [12,19]. SLC7A7 encodes the y + L amino acid transporter-1 (y + LAT-1), which is responsible for the transport of dibasic amino acids at the basolateral membrane of epithelial cells in the intestines and kidneys.…”