UBA3

Last update 08 May 2025

Basic Info

Synonyms

hUba3, NAE2, NEDD8-activating enzyme E1 catalytic subunit

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Introduction

Catalytic subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Down-regulates steroid receptor activity. Necessary for cell cycle progression.

100 Clinical Results associated with UBA3

100 Translational Medicine associated with UBA3

0 Patents (Medical) associated with UBA3

Literatures (Medical) associated with UBA3

01 May 2025·Biochemical and Biophysical Research Communications

Neddylation as a target in PIK3CA-mutated head and neck cancer

Article

Author: Hua Fu, Becky Xu ; VanLandingham, Nathan K ; Grandis, Jennifer R ; Izgutdina, Adila ; Gilbert, Luke A ; Woerner, Liam C ; Cui, Zhibin ; Nazarenko, Andrew ; Johnson, Daniel E ; Naara, Shorook

PIK3CA encodes the catalytic subunit of phosphoinositide 3-kinase (PI3K) enzyme and is the most commonly mutated oncogene in head and neck squamous cell carcinoma (HNSCC). This study aimed to identify potential therapeutic targets in HNSCC harboring mutant PIK3CA. We used CRISPR interference (CRISPRi)-based genome-wide screening methodology to reveal targetable genetic dependencies in PIK3CA-mutated HNSCC. Screening was conducted in an HPV-positive HNSCC cell line, UM-SCC-47, engineered to express the canonical E545K PIK3CA mutant. We identified 34 genes co-dependent on PIK3CA E545K mutation, including 5 genes in the neddylation pathway (NEDD8, NEDD8-MDP-1 and NAE1, USP8, UBA3). Validation experiments confirmed the essential role of NEDD8, NEDD8-MDP-1, and NAE1, indicating a novel regulatory mechanism in PIK3CA E545K-mutated HNSCC. Our findings suggest that PIK3CA mutation may serve as a predictive biomarker for neddylation inhibitor therapy in a subpopulation of HNSCC.

01 Mar 2025·European Journal of Pharmacology

Camk2n1 deficiency reduces the NaCl cotransporter activity through the CUL3/KLHL3/WNK4 complex in the kidney

Article

Author: Zhang, Zihao ; Zhang, Chong ; Zhang, Ya ; Jiang, Gengru

Calcium/calmodulin dependent protein kinase II inhibitor 1 (Camk2n1) is closely associated with a peak logarithm of odds score in quantitative trait loci for systolic blood pressure. Increased Camk2n1 mRNA expression has been specifically observed in the kidneys of hypertension mouse models. However, the precise role of Camk2n1 in the kidney remains unclear. We generated Camk2n1-/- mice using the CRISPR/Cas9 system. Compared to controls, Camk2n1-/- mice exhibited consistently lower systolic blood pressure across all measured time points. Deletion of Camk2n1 resulted in decreased apical labeling of phosphorylated and total thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule. NCC phosphorylation is regulated by activated SPAK/OSR1 kinases, which act downstream of With-No-lysine (K) kinase (WNK). In Camk2n1-/- mice, the elevated abundances of key components of the Cullin 3 (CUL3) RING ubiquitin ligase, including neddylated CUL3 and the adaptor Kelch-like protein 3, promoted proteasomal degradation of WNK4. In renal tissues, Camk2n1 deletion led to increased mRNA and protein levels of ubiquitin-like modifier-activating enzyme 3 (UBA3) and ubiquitin-conjugating enzyme E2 (UBE2M). Conversely, Camk2n1 overexpression in HEK293 cells resulted in decreased levels of UBA3 and UBE2M, along with reduced CUL3 neddylation. Treatment with MLN4924 effectively suppressed CUL3 hyperneddylation and restored WNK4 levels in the kidneys of Camk2n1-/- mice. In summary, Camk2n1 deletion lowers blood pressure, likely by promoting WNK4 degradation through dysregulated CUL3 RING ubiquitin ligase activity, which leads to decreased NCC activity.

01 Nov 2024·Biochemical Pharmacology

The blockade of neddylation alleviates ventilator-induced lung injury by reducing stretch-induced damage to pulmonary epithelial cells

Article

Author: Lin, Chin-Kuo ; Huang, Tzu-Hsiung ; Lin, Chieh-Mo ; Chang, Shun-Fu ; Shi, Chung-Sheng

Ventilator-induced lung injury is a serious complication in mechanically ventilated patients. Neddylation, the post-translational modification of neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) conjugation, regulates numerous biological functions. However, its involvement and therapeutic significance in ventilator-induced lung injury remains unknown. Therefore, this study aimed to examine the kinetics and contribution of activated neddylation and the impact of neddylation inhibition in mice subjected to high tidal volume (HTV) ventilation in vivo and human pulmonary alveolar epithelial cells stimulated through cyclic stretching (CS) in vitro. The neddylation and expression of ubiquitin conjugating enzyme 3 (UBA3), a NEDD8-activating enzyme (NAE) catalytic subunit, were time-dependently upregulated in HTV-ventilated mice. Additionally, the NAE inhibitor MLN4924 considerably attenuated acute lung injury induced by HTV ventilation, manifesting as reduced inflammation and oxidative stress. Furthermore, MLN4924 effectively reduced the secretion of inflammatory cytokines from Ly6C^high monocytes and neutrophils, subsequently decreasing endothelial permeability. Moreover, our study revealed an upregulation of the neddylation pathway, oxidative stress, and apoptosis during CS of alveolar epithelial cells. However, blockade of neddylation via MLN4924 or through UBA3 knockdown suppressed this upregulation. Overall, the inhibition of neddylation may alleviate HTV-induced acute lung injury by preventing CS-induced damage to alveolar epithelial cells. This indicates that the neddylation pathway plays a critical role in the progression of ventilator-induced lung injury. These findings may provide a new therapeutic target for treating ventilator-induced lung injury.

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UBA3

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