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Last update 08 May 2025

NAE1

Last update 08 May 2025

Basic Info

Synonyms

Amyloid beta precursor protein-binding protein 1, 59 kDa, Amyloid protein-binding protein 1, APP-BP1

+ [6]

Introduction

Regulatory 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. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. The covalent attachment of NEDD8 to target proteins is known as 'neddylation' and the process is involved in the regulation of cell growth, viability and development.

Drugs associated with NAE1

BSCHL-2046

Target

NAE1 x Ubiquitin-protein ligases

Mechanism

NAE1 modulators [+2]

Active Org.

University of California

Originator Org.

University of California

Active Indication

Prostatic Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

X-10

Target

NAE1

Mechanism

NAE1 modulators

Active Org.

Zhengzhou University

Originator Org.

Zhengzhou University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

LP0040

Target

NAE1 x UBA1

Mechanism

NAE1 inhibitors [+1]

Active Org.-

Originator Org.

Nanjing Tech University

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with NAE1

NCT04661644

/ CompletedPhase 1/2

A Phase 1/2a Clinical Trial to Evaluate the Efficacy and Safety of Allogenic Adipose Tissue-derived Mesenchymal Stem Cell Clusters in Patients with Critical Limb Ischemia

This clinical trial is designed as a Phase 1/2a clinical trial targeting patients with critical limb ischemia. The trial is composed of Phase 1 to assess the tolerability and safety and Phase 2a to assess the safety and efficacy of the investigational product(A cluster of adipose-derived mesenchymal stem cells (3D-A) (cluster of adipose- derived mesenchymal stem cells)) and proceeds in that order.

Start Date04 Nov 2020

Sponsor / Collaborator

S.Biomedics Co., Ltd.

[+1]

100 Clinical Results associated with NAE1

100 Translational Medicine associated with NAE1

0 Patents (Medical) associated with NAE1

139

Literatures (Medical) associated with NAE1

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.

11 Mar 2025·Proceedings of the National Academy of Sciences

The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8 ⁺ T cells

Article

Author: Novais, Fernanda ; Bucci, Donna ; Xiao, Min ; Jin, Jiacheng ; Zhu, Jiangjiang ; Huang, Stanley Ching-Cheng ; Sun, Nuo ; Gao, Fengxia ; Wang, Yi ; Yu, Yanbao ; Lio, Jerry ; Xin, Gang ; Ghoneim, Hazem ; Zhang, Ruohan ; Li, Zihai ; Liao, Zhiwei ; Wen, Haitao ; Li, Jianying ; Gao, Shuaixin ; Ma, Ruilin ; Ma, Qin

Optimal activation of CD8+ T cells is crucial for immunity-mediated destruction of cancer, requiring a substantial amount of proteins involved in metabolism, proliferation, and effector function. Despite extensive studies emphasizing the role of transcriptional regulation in this process, paired transcriptomic and proteomic analyses reveal that the RNA profile is poorly correlated with protein levels. This discrepancy underscores the importance of post-translational modifications (PTMs) in controlling protein abundance during activation. However, the impact of PTMs on the CD8+ T cell protein dynamic remains underexplored. We identify that neddylation, a recently discovered PTM, is activated in response to T cell receptor (TCR) stimulation and enriched in effector CD8+ T cells from colon cancer patients. Mechanistically, we found the rate-limiting enzyme of neddylation, neural precursor cell expressed developmentally down-regulated protein 8 activating enzyme E1 (NAE1), is induced by the NFATc1, a critical transcription factor downstream of TCR signaling. Our observation revealed that genetic ablation of NAE1 significantly disturbed the proteomic landscape related to activation and mitochondrial function. As a result, CD8+ T cells lacking NAE1 exhibited severely compromised activation, proliferation, and survival, which was accompanied by impaired mitochondrial function. Consistently, deletion of NAE1 in CD8+ T cells abolished their antitumor function and promoted tumor progression. By contrast, the overexpression of NAE1 significantly improved the function of tumor-infiltrating CD8+ T cells. Overall, we uncovered neddylation, a previously underappreciated PTM, as a proteomic checkpoint for CD8+ T cell activation. Enforced expression of NAE1 offers promising therapeutic potential for boosting the antitumor CD8+ T cell responses.

12 Feb 2025·Clinical Science

Blockade of neddylation through targeted inhibition of DCN1 alleviates renal fibrosis

Article

Author: Liu, Zhangsuo ; Huo, Jin-Ling ; Feng, Qi ; Pan, Shaokang ; Liu, Dongwei ; Fu, Wenjia

Neddylation is a process of attaching neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to substrates for the protein function modulation via enzymatic cascades involving NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligase (E3). Defective in cullin neddylation 1 (DCN1) serves as a co-E3 ligase, which can simultaneously bind E2 UBE2M and cullin proteins to stabilize the catalytic center of the Cullin-Ring E3 ligase complex, thereby promoting cullin neddylation. Neddylation is reported to be activated in diverse human diseases, and inhibition of protein neddylation has been regarded as a promising anticancer therapy. However, whether neddylation participates in renal fibrosis and whether blockade of neddylation through targeted inhibition of DCN1 play effects on renal fibrosis remains unknown. In the present study, an NEDD8 overexpressed plasmid, DCN1 small interfering RNAs, DCN1-specific inhibitor NAcM-OPT, human renal tubular epithelial cells (HK-2), rat kidney fibroblasts (NRK-49F), RNA sequencing, unilateral ureteral obstruction (UUO), and unilateral ischemia-reperfusion injury (UIRI) mouse renal fibrosis models were used. Herein, we first showed that neddylation was activated in renal fibrosis. Neddylation blockade through DCN1 deficiency alleviated TGFβ1-induced up-regulation of fibronectin and α-SMA in HK-2 and NRK-49F cells. Importantly, DCN1 inhibition attenuated UUO- and UIRI-induced mouse renal fibrosis. Further studies revealed that DCN1 loss selectively inhibited cullin3 neddylation and induced its substrate NRF2 accumulation, thereby inhibiting TGFβ-Smad2/3 signaling pathway. Overall, blockade of neddylation through targeted inhibition of DCN1 contributes to alleviating renal fibrosis in vitro and in vivo, which may constitute a novel therapeutic strategy for renal fibrosis.

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NAE1

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