Role of neddylation in neurological development and diseases

He, Xin; Zhu, Ainong; Feng, Jianguo; Wang, Xiaobin

doi:10.1002/bab.2112

Cited by 25 publications

(11 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CUL3 normally undergoes covalent modification by addition (catalyzed by NEDD8-activating enzyme) and then removal (catalyzed by c-Jun activation domain-binding protein-1, JAB1), of the 9KDa ubiquitin-like protein NEDD8. This cycling of NEDD8 addition/removal (“neddylation”/“deneddylation”) is essential for the stability and activity of the CRL, and has been shown to be physiologically important in multiple organs including the heart, 11 the brain, 12 and the immune system 13 . In the kidney, recent evidence from studies in mice suggests that cullin neddylation status changes in response to dietary potassium, 6 or in models of diabetes 14 , 15 .…”

mentioning

confidence: 99%

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Maeoka

Ferdaus

Cornelius

et al. 2022

JASN

View full text Add to dashboard Cite

Background: Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease Familial Hyperkalemic Hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Δ9) increases abundance of With-No-Lysine [K] Kinase 4 (WNK4), inappropriately activating Sterile 20/SPS-1-related proline/alanine-rich kinase (SPAK), which then phosphorylates and hyperactivates the Na+-Cl- cotransporter (NCC). The precise mechanism by which CUL3-Δ9 causes FHHt has been unclear. We tested the hypothesis that reduced abundances of CUL3 and of Kelch-like 3 (KLHL3), the CUL3 substrate adaptor for WNK4, are mechanistically important. Since JAB1, an enzyme that inhibits CUL3 activity by removing the ubiquitin-like protein NEDD8, cannot interact with CUL3-Δ9, we also determined whether Jab1 disruption mimicked the effects of CUL3-Δ9 expression. Methods: We used an inducible renal tubule-specific system to generate several mouse models expressing CUL3-Δ9, mice heterozygous for both CUL3 and KLHL3 (Cul3+/−/Klhl3+/−), and mice with short-term Jab1 disruption (to avoid renal injury associated with long-term disruption). Results: Renal KLHL3 was higher in Cul3−/− mice, but lower in Cul3−/−/Δ9 mice and in the Cul3+/−/Δ9 FHHt model, suggesting KLHL3 is a target for both WT and mutant CUL3. Cul3+/−/Klhl3+/− mice displayed increased WNK4-SPAK activation and phospho-NCC abundance, and an FHHt-like phenotype with increased plasma [K+] and salt-sensitive blood pressure. Short-term Jab1 disruption in mice lowered abundances of CUL3 and KLHL3, and increased abundances of WNK4 and phospho-NCC. Conclusions:Jab1-/- mice and Cul3+/−/Klhl3+/− mice recapitulated the effects of CUL3-Δ9 expression on WNK4-SPAK-NCC. Our data suggest that degradation of both KLHL3 and CUL3 plays a central mechanistic role in CUL3-Δ9-mediated FHHt.

show abstract

mentioning

confidence: 99%

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Maeoka

Ferdaus

Cornelius

et al. 2022

JASN

View full text Add to dashboard Cite

show abstract

“…However, to date, the relevance of hnRNPA2B1 as a potential therapeutic target has not been tested in clinical trials. In contrast, several clinical trials examining the therapeutic potential of neddylation inhibitors against cancer [ 42 , 43 ], as well as in neurological diseases [ 44 ] are in progress. Future studies will help determine whether neddylation inhibitors may be a beneficial therapeutic approach for HTGP, potentially through the regulation of hnRNPA2B1.…”

Section: Discussionmentioning

confidence: 99%

Neddylation-mediated degradation of hnRNPA2B1 contributes to hypertriglyceridemia pancreatitis

et al. 2022

View full text Add to dashboard Cite

Hypertriglyceridemia-induced acute pancreatitis (HTGP) is characterized by the acute and excessive release of FFA produced by pancreatic lipases. However, the underlying mechanisms of this disease remain poorly understood. In this study, we describe the involvement of the RNA binding protein hnRNPA2B1 in the development of HTGP. We used palmitic acid (PA) and AR42J cells to create a model of HTGP in vitro. RT-PCR and western blot analyses revealed a decrease in the level of hnRNPA2B1 protein but not mRNA expression in PA-treated cells. Further analyses revealed that hnRNPA2B1 expression was regulated at the post-translational level by neddylation. Restoration of hnRNPA2B1 expression using the neddylation inhibitor MLN4924 protected AR42J cells from PA-induced inflammatory injury by preventing NF-κB activation and restoring fatty acid oxidation and cell proliferation. Furthermore, RNA immunoprecipitation studies demonstrated that hnRNPA2B1 orchestrates fatty acid oxidation by regulating the expression of the mitochondrial trifunctional protein-α (MTPα). Administration of MLN4924 in vivo restored hnRNPA2B1 protein expression in the pancreas of hyperlipidemic mice and ameliorated HTGP-associated inflammation and pancreatic tissue injury. In conclusion, we show that hnRNPA2B1 has a central regulatory role in preventing HTGP-induced effects on cell metabolism and viability. Furthermore, our findings indicate that pharmacological inhibitors that target neddylation may provide therapeutic benefits to HTGP patients.

show abstract

“…In a work by Jegga et al [ 67 ], via a systems biology approach a significant number of genes have been identified for their involvement of ALP, from which 23 are currently highlighted in our own results ( HDAC6 , MTOR , NFKB1 , ITPR1 , TSC1 , LRP2 , PRKCD , SORT1 , ESR1 , MAPK8 , MYC , DAPK1 , TP63 , MAPK1 , NRG1 , ERN1 , FOXO3 , ITGB1 , ATG5 , AKT1 , RPS6KB1 , BECN1 , BCL2L1 ). Furthermore, synaptic plasticity and excitatory transmission are regulated by neuronal neddylation, which contributes to nerve growth, synapse strength, neurotransmission, and synaptic plasticity at normal levels, but the overactivation of protein neddylation pathways leads to apoptosis, neuronal autophagy, and tumor growth [ 68 ]. This knowledge enhances our findings that neddylation related genes are highly correlated to memory function in AD.…”

Section: Discussionmentioning

confidence: 99%

Unlocking the Memory Component of Alzheimer’s Disease: Biological Processes and Pathways across Brain Regions

et al. 2022

View full text Add to dashboard Cite

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and a general cognitive decline leading to dementia. AD is characterized by changes in the behavior of the genome and can be traced across multiple brain regions and cell types. It is mainly associated with β-amyloid deposits and tau protein misfolding, leading to neurofibrillary tangles. In recent years, however, research has shown that there is a high complexity of mechanisms involved in AD neurophysiology and functional decline enabling its diverse presentation and allowing more questions to arise. In this study, we present a computational approach to facilitate brain region-specific analysis of genes and biological processes involved in the memory process in AD. Utilizing current genetic knowledge we provide a gene set of 265 memory-associated genes in AD, combinations of which can be found co-expressed in 11 different brain regions along with their functional role. The identified genes participate in a spectrum of biological processes ranging from structural and neuronal communication to epigenetic alterations and immune system responses. These findings provide new insights into the molecular background of AD and can be used to bridge the genotype–phenotype gap and allow for new therapeutic hypotheses.

show abstract

Role of neddylation in neurological development and diseases

Cited by 25 publications

References 108 publications

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice

Neddylation-mediated degradation of hnRNPA2B1 contributes to hypertriglyceridemia pancreatitis

Unlocking the Memory Component of Alzheimer’s Disease: Biological Processes and Pathways across Brain Regions

Contact Info

Product

Resources

About