NAE1 (NEDD8 Activating Enzyme E1 Subunit 1)

Cardiac neddylation preserves adult heart function by coordinating mitochondrial fusion-fission dynamics and sustaining cullin-dependent ubiquitination and turnover of damaged mitochondria. These findings identify neddylation as a key regulator of mitochondrial quality control and link its disruption to human cardiomyopathy. Therapeutically, targeting the neddylation-cullin axis may limit mitochondrial dysfunction, enhance mitophagy, and improve energetic reserve in failing hearts, while neddylation signatures in patient myocardium may help guide stratification and precision therapy for cardiomyopathy.

Moreover, H. pylori infection inhibited erastin-induced ferroptosis of gastric cancer cells...pylori infection mediates malignant behaviors of gastric cancer via inactivating NAE1/TFR1 signaling. Therefore, targeting NAE1/TFR1 signaling may provide a novel strategy for gastric cancer.

Furthermore, we found that NAE1 depletion suppressed proliferation, migration, and invasion of HCC cells in vitro experiments. In conclusion, NAE1 protein holds considerable potential as a valuable biomarker for predicting clinical outcomes, immune landscapes, and drug sensitivity in HCC, as well as a promising therapeutic target.

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.

However, in vitro and in vivo experiments demonstrate that inhibiting NAE1 with MLN4924 leads to increased resistance of NPC to radiation. Targeting NAE1 for NPC treatment may have dual effects, inhibiting NPC proliferation while also increasing radiation resistance.

P2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025

We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.