Ask about this productRelated genes to: NEDD8 protein
- Gene:
- NEDD8 NIH gene
- Name:
- NEDD8 ubiquitin like modifier
- Previous symbol:
- -
- Synonyms:
- Nedd-8
- Chromosome:
- 14q12
- Locus Type:
- gene with protein product
- Date approved:
- 1994-01-21
- Date modifiied:
- 2019-04-04
Related products to: NEDD8 protein
Related articles to: NEDD8 protein
- Plant Cullin RING Ubiquitin E3 ligases (CRLs) play a critical role in targeted protein degradation, essential for physiological development and stress adaptation. The deneddylase activity of the COP9 signalosome (CSN) tightly regulates the cellular balance of neddylated cullins, which is crucial for maintaining the full spectrum of CRL functions. Although selective inositol polyphosphates (InsPs) act as cofactors in plant responses that involve ubiquitylation of negative regulators, their connection to CSN-CRL activities has remained unclear. In this study, we reveal that the two Arabidopsis thaliana InsP-kinases, IPK1 and ITPK1, physically interact and orchestrate the metabolic regulation of the CSN holo-complex activity. Notably, ITPK1 deficiency lowers Nedd8 processing rates, elevates the cellular ratios of neddylated cullins, and disturbs the dissociation equilibrium of CSN5 and CUL1 from the holo-complex. These findings uncover a novel autoregulatory switch in CSN functions, governed by deneddylation activity. Furthermore, we demonstrate that the phosphate starvation response (PSR), induced in phosphate-limited wild-type plants and constitutively active in the InsP-kinase mutants, is partly regulated by reduced deneddylation rates, which affect the stability of SPX4, a key negative regulator of PSR. Pharmacological inhibition of cullin neddylation stabilizes SPX4 and impairs PSR, thereby linking CSN-CRL dynamics to phosphate sensing. Conversely, pharmacologically inhibiting CSN5 deneddylase activity causes wild-type plants to exhibit PSR phenotypes similar to those of the InsP-kinase mutants. Collectively, these results reveal that specific InsP-kinases are partly involved in modulating plant PSR by fine-tuning the coordination between CRL and CSN activities. - Source: PubMed
Publication date: 2026/05/05
Walia YashikaNoopur MedhaBhattacharya IshanaSahoo Bhaskar ChandraKasera MritunjayPullagurla Naga JyothiDutta SmritikanaLiu GuizhenSchaaf GabrielJessen HenningLaha DebabrataBhattacharjee SouvikBhattacharjee Saikat - As the core scaffold protein of the Cullin-RING ligase 5 (CRL5) complex, CUL5 regulates the stability of multiple substrate proteins through the ubiquitin-proteasome system (UPS), playing a crucial role in the initiation, progression, and cellular therapy of malignant tumors. This review systematically elaborates the context-dependent role, molecular regulatory network, and therapeutic targeting potential of CUL5-mediated ubiquitination in cancer cell therapy. The activity of CUL5 is highly dependent on NEDD8-mediated neddylation, and its dysregulation indirectly influences tumor cell proliferation, apoptosis, metabolic reprogramming, angiogenesis, and the immune microenvironment by modulating key signaling pathways such as NOXA, mTORC, TRAF6/NF-κB, and JAK/STAT. Notably, CUL5 exhibits dual regulatory functions in various cancers, and its expression level correlates differently with prognosis depending on tumor type. In recent years, the development of inhibitors and nano-delivery systems targeting CUL5 and its related pathways has provided novel strategies for precisely targeting CUL5. Moreover, in adoptive cell therapies (e.g., CAR-T, TCR-T, CAR-NK), modulation of CUL5 expression can significantly enhance immune-cell proliferation, cytokine secretion, and anti-tumor efficacy. This article summarizes the multidimensional role of CUL5 in tumor cell therapy and prospects its potential as a novel therapeutic target in combined therapies and precision medicine. - Source: PubMed
Publication date: 2026/04/17
Lu YuanchenQian YichenMa YueShao XianhuaXie Jianjun - Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and one of the best-characterized drivers is oncogenic Wnt signaling. In this study, we demonstrated that Orlistat, an FDA-approved anti-obesity drug, is a unique inhibitor of oncogenic Wnt signaling and CRC. We confirmed that the known target FASN was not associated with Orlistat inhibition of CRC, and identified the NEDD8-conjugating enzyme UBC12 (UBE2M) as a candidate target instead. The direct engagement of Orlistat and UBC12 was confirmed by ITC assay with a KD value of 678 nM. Of note, Orlistat inhibited the NEDD8-conjugating activity of UBC12 and blocked UBC12 interaction with DCN1 (defective in cullin neddylation 1), thereby selectively suppressing Cullin 1 neddylation. In addition, overexpression of UBC12 positively regulated Wnt/β-catenin signaling in normal cells, while depletion of UBC12 not only inhibited oncogenic Wnt signaling but also abrogated Orlistat's inhibition of Wnt signaling and cell proliferation in CRC cells. Taken together, our findings revealed UBC12 as a novel Orlistat target, and identified UBC12 as a potential therapeutic target for Wnt-dependent cancers. - Source: PubMed
Publication date: 2026/04/30
Shen MengzhenLi HuihuiXuan YingZhu HongyanChen LizheHao PiliangZhang ChengqianFang JiansongZhou XianglianYan RongQu YiKe Xisong - The NEDD8-activating enzyme (NAE), comprising NAE1 and UBA3, is an anticancer target. The relative contribution of each of these subunits toward NAE inhibitor (NAEi) efficacy remains unclear. We demonstrated a profound interdependence of NAE1 and UBA3 expression. UBA3 reduction augmented NAEi sensitivity, whereas its overexpression led to decreased sensitivity. deficiency enhanced RKO xenograft sensitivity to SOMCL-19-133 (NAEi), which was reversed by UBA3 restoration. Cells with naturally low UBA3 expression were highly NAEi-sensitive. The criticality of UBA3 in NAEi sensitivity is not completely unexpected given that the ability of NAEi to directly bind to UBA3 is known. TCGA data showed that rectum adenocarcinoma patients with low mRNA had poorer prognoses, and 27.16% of tumors expressed low mRNA. We propose that low expression may serve as a NAEi sensitivity biomarker, particularly given that MLN4924 (NAEi) phase 3 failures may be due to a lack of patient stratification. Therefore, our key findings, on the criticality of UBA3 in NAEi sensitivity, underpin future clinical evaluations. - Source: PubMed
Publication date: 2026/04/29
Miao Yu-LingZhou Li-NaSong Shan-ShanBao Xu-BinHuan Xia-JuanDing JianHe Jin-Xue - Natural killer (NK) cell-based therapies are a promising approach in cancer, but their efficacy is limited by impaired effector function and tumor-intrinsic resistance. To systematically identify therapeutic strategies that target both sides of the cancer-immune interface, we designed a multimodal immunopharmacologic screening platform comprising high-throughput co-culture drug screens, cytokine secretome profiling, single-cell perturbation screens, and genome-scale CRISPR screening, followed by validation in biobanked patient-derived models. Applying the platform across five blood cancer types, we identified protein kinase C (PKC) activation to simultaneously increase effector cytotoxicity and cytokine secretion through transcriptomic rewiring, and tumor susceptibility to NK cell killing through tumor-intrinsic PKC-δ. In patient samples, PKC activation sensitized NK-resistant leukemic progenitors to NK cell killing. In addition, NEDD8 inhibition enhanced NK function and shifted tumor TNF signaling towards pro-apoptotic pathways. Our platform provides a systematic approach to identify drugs rewiring both sides of the cancer-immune interface to circumvent tumor immune resistance. - Source: PubMed
Publication date: 2026/04/17
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