UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism

Abstract

The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences (''N-end rule''). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7.Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

“…Like CHIP, UBR1, and UBR7, whose deficiencies reportedly cause the Johanson-Blizzard ( Zenker et al, 2005 ) and Li-Campeau syndromes ( Li et al, 2021 ), respectively, are E3 ubiquitin ligases with multiple potential substrates. As members of the N-end rule pathway, UBR1 and UBR7 target any protein carrying N-terminal destabilizing motifs (also referred to as “N-degrons”) such as arginine residues for degradation ( Varshavsky, 2019 ).…”

Regulation of Notch signaling by E3 ubiquitin ligases

“…Recently, autosomal recessive mutations in another Ubr family gene, UBR7, were reported in patients with developmental delay, intellectual disability, and seizure [155]. Further genetic studies in C. elegans deciphered an influence of Ubr-5 and Ubr-7 on Notch signaling during its development [155]. Interestingly, in some cases, abnormal E3 Ub ligase activity directly affects Notch signaling, whereas, in several instances, there is no obvious link between the abnormal activity of the E3 ligase and Notch pathway in disease manifestation [133,144,146,[156][157][158][159] (Table 1 provides a detailed depiction of defective E3 ligase activity and human diseases).…”

“…However, the mechanism of Notch regulation by UBR1/UBR2 is not clear. Recently, autosomal recessive mutations in another Ubr family gene, UBR7 , were reported in patients with developmental delay, intellectual disability, and seizure [155]. Further genetic studies in C. elegans deciphered an influence of Ubr‐5 and Ubr‐7 on Notch signaling during its development [155].…”

E3 Ubiquitin Ligases in Breast Cancer Metastasis: A Systematic Review of Pathogenic Functions and Clinical Implications

“…The UBR-box is a 70-residue zinc finger domain present in the UBR family of E3 ubiquitin ligases. Unlike UBR5, which also contains an HECT domain, the structures responsible for UBR7 executing its E3 role need to be verified by in vitro ubiquitin assays (113,131,132). Intriguingly, UBE2O, an E2/E3 hybrid ubiquitin-protein ligase, displays both E2 ubiquitin conjugating enzyme and E3 ubiquitin ligase activities (116,133).…”