Protein neddylation and its role in health and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 4, 2024

Abstract NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like that covalently attached to a lysine residue of substrate through process known as neddylation, catalyzed by the enzyme cascade, namely activating (E1), conjugating (E2), and ligase (E3). The substrates neddylation are categorized into cullins non-cullin proteins. Neddylation activates CRLs (cullin RING ligases), largest family E3 ligases, whereas alters their stability activity, well subcellular localization. Significantly, pathway and/or many abnormally activated or over-expressed in various human diseases, such metabolic disorders, liver dysfunction, neurodegenerative cancers, among others. Thus, targeting becomes attractive strategy for treatment these diseases. In this review, we first provide general introduction on its biochemical regulation, crystal structures enzymes complex with cullin substrates; then discuss how governs key biological processes via modification substrates. We further review literature data dysregulated several particularly cancer, followed outline current efforts discovery small molecule inhibitors promising therapeutic approach. Finally, few perspectives were proposed extensive future investigations.

Language: Английский

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PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 4, 2024

Immunotherapy has been developed, which harnesses and enhances the innate powers of immune system to fight disease, particularly cancer. PD-1 (programmed death-1) PD-L1 death ligand-1) are key components in regulation system, context cancer immunotherapy. regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation glycosylation. PROTACs (Proteolysis Targeting Chimeras) a type new drug design technology. They specifically engineered molecules that target specific proteins within cell for degradation. have designed demonstrated their inhibitory activity against PD-1/PD-L1 pathway, showed ability degrade proteins. In this review, we describe how improve efficacy could be novel strategy combine with radiotherapy, chemotherapy immunotherapy patients.

Language: Английский

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Neddylation Regulation of Immune Responses

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Neddylation plays a vital role in post-translational modification, intricately shaping the regulation of diverse biological processes, including those related to cellular immune responses. In fact, neddylation exerts control over both innate and adaptive systems via various mechanisms. Specifically, influences function survival cells, activation pattern recognition receptors GMP-AMP synthase–stimulator interferon genes pathways, as well release cytokines reactions. Moreover, also governs antigen-presenting which are crucial for initiating addition, regulates T cell activation, proliferation, differentiation, survival, their effector functions, thereby ensuring an appropriate response. this review, we summarize most recent findings these aspects delve into connection between dysregulated events immunological disorders, especially inflammatory diseases. Lastly, propose future directions potential treatments diseases by targeting neddylation.

Language: Английский

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The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Neddylation is necessary for activation of Cullin-RING ligases (CRLs), which degrade various immune regulatory proteins. Our recent study showed that while depletion neddylation E2-E3 pair Ube2f-Sag in T (Treg) cells had no obvious phenotype, the same either Ube2m or Rbx1 caused inflammation disorders with different severity. Whether these E2s E3s compensate each other functional regulations Treg is, however, previously unknown. In this report, we generated Foxp3Cre;Ube2mfl/fl;Ube2ffl/fl Foxp3Cre;Rbx1fl/fl;Sagfl/fl double-null mice by simultaneous deletion both cells, respectively. Remarkably, Ube2m&Ube2f developed much severe autoimmune phenotypes than did Ube2m-null mice, indicating markedly compensates Ube2f cells. The minor worsened seen at very early stage Rbx1&Sag Rbx1-null likely due to already later, a compensation Sag. RNA profiling-based analyses revealed up- and down-regulations few signaling pathways are associated severity phenotypes. Finally, severer double E3-null E2-null indicate neddylation-independent mechanism 2 E3s, also known serve as RING component CRLs regulation cell fitness.

Language: Английский

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Research progress of LSD1-based dual-target agents for cancer therapy

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 101, P. 117651 - 117651

Published: Feb. 21, 2024

Language: Английский

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Cullin-Conciliated Regulation of Plant Immune Responses: Implications for Sustainable Crop Protection

Plants, Journal Year: 2024, Volume and Issue: 13(21), P. 2997 - 2997

Published: Oct. 26, 2024

Cullins are crucial components of the ubiquitin–proteasome system, playing pivotal roles in regulation protein metabolism. This review provides insight into wide-ranging functions cullins, particularly focusing on their impact plant growth, development, and environmental stress responses. By modulating cullin-mediated mechanisms, researchers can fine-tune hormone-signaling networks to improve various agronomic traits, including architecture, flowering time, fruit nutrient uptake. Furthermore, targeted manipulation cullins that involved pathways, e.g., cytokinin, auxin, gibberellin, abscisic acids, ethylene, boost crop growth development while increasing yield enhancing tolerance. also play important defense mechanisms through regulating defense-associated metabolism, thus boosting resistance pathogens pests. Additionally, this highlights potential integrating cullin-based strategies with advanced biological tools, such as CRISPR/Cas9-mediated genome editing, genetic engineering, marker-associated selections, gene overexpression, knockout, achieve precise modifications for improvement sustainable agriculture, promise creating resilient, high-yielding, environmentally friendly varieties.

Language: Английский

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Regular or DCAF2: How CRL4DCAF2 Affects IBD-Related Mucosal Injury

Digestive Diseases and Sciences, Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 15, 2023

Language: Английский

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