Protein neddylation and its role in health and diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Апрель 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.

Язык: Английский

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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Янв. 15, 2024

Abstract Systemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response, autoantibody accumulation and damage to organs. The dysregulation of double-negative (DN) T cells considered as crucial commander during SLE. Neddylation, significant type protein post-translational modification (PTM), has been well-proved regulate cell-mediated immune response. However, the function neddylation in SLE still unknown. Here, we reported that inactivation with MLN4924, specific inhibitor NEDD8-activating enzyme E1 (NAE1), or genetic abrogation Ube2m decreased DN cell attenuated murine development. Further investigations revealed blocked Bim ubiquitination degradation maintained level cells, contributing apoptosis accumulated mice. Then double knockout (KO) lupus-prone mice ( -/- lpr ) were generated results showed loss reduced deficiency-induced reversed alleviated progression. Our findings identified promoted Bim-mediated Clinically, also found patients, proportion was raised their reduced. Moreover, compared healthy groups, patients exhibited levels elevated Cullin1 levels. Meantime, inhibition induced Bim-dependent isolated from patients. Altogether, our provide direct evidence about lupus, suggesting promising therapeutic approach for this disease.

Язык: Английский

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Neddylation Regulation of Immune Responses

Research, Год журнала: 2023, Номер 6

Опубликована: Янв. 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.

Язык: Английский

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What is the relevance of FoxP3 in the tumor microenvironment and cancer outcomes?

Expert Review of Clinical Immunology, Год журнала: 2024, Номер 20(8), С. 803 - 809

Опубликована: Март 21, 2024

Forkhead box P3 (FoxP3) transcription factor plays critical roles in controlling immune responses and cancer progression different cancers. FoxP3 expression within the tumor microenvironment (TME) may influence clinical outcomes negatively or positively, it could play dual cancer, either by promoting inhibiting development progression. Some studies reported that high levels of be associated with worse prognosis, while others contradictory results.

Язык: Английский

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Discovery of small molecule inhibitors of neddylation catalyzing enzymes for anticancer therapy

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 179, С. 117356 - 117356

Опубликована: Авг. 29, 2024

Protein neddylation, a type of post-translational modifications, involves the transfer ubiquitin-like protein NEDD8 to lysine residues target substrate, which is catalyzed by activating enzyme (E1), conjugating (E2), and ligase (E3). Cullin family proteins, core components Cullin-RING E3 ubiquitin ligases (CRLs), are most well-known physiological substrates neddylation. CRLs, activated upon cullin promote ubiquitination variety key signaling proteins for proteasome degradation, thereby regulating many critical biological functions. Abnormal activation neddylation enzymes as well CRLs has been frequently observed in various human cancers associated with poor prognosis cancer patients. Consequently, targeting emerged promising strategy development novel anticancer therapeutics. This review first briefly introduces properties its role cancer, then systematically summarizes all reported chemical inhibitors three enzymes, providing focused, up date, comprehensive resource discovery these small molecule inhibitors.

Язык: Английский

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Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis

Research, Год журнала: 2024, Номер 7

Опубликована: Янв. 1, 2024

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features infiltration mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) considered a double-edged sword inflammation-associated diseases, but its function clinical relevance H. -associated pathology are unknown. Here, we demonstrate both pro-colonization pro-inflammation roles ANGPTL4 infection. Increased the infected mucosa was produced from epithelial (GECs) synergistically induced by IL-17A cagA -dependent manner. Human correlated colonization severity gastritis, mouse non-bone marrow-derived promoted bacteria inflammation. Importantly, inflammation were attenuated Il17a −/− , Angptl4 mice. Mechanistically, bound to integrin αV (ITGAV) on GECs suppress CXCL1 production inhibiting ERK, leading decreased influx neutrophils, thereby promoting colonization; also ITGAV monocytes promote CCL5 activating PI3K–AKT–NF-κB, resulting increased regulatory CD4 + T (T regs ) via CCL5–CCR4-dependent migration. In turn, reg proliferation binding activate gastritis. Overall, propose model which collectively ensures promotes Efforts inhibit ANGPTL4-associated pathway may prove valuable strategies treating

Язык: Английский

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Anti-TNFR2 Antibody-Conjugated PLGA Nanoparticles for Targeted Delivery of Adriamycin in Mouse Colon Cancer

Research, Год журнала: 2024, Номер 7

Опубликована: Янв. 1, 2024

High levels of tumor necrosis factor receptor type II (TNFR2) are preferentially expressed by immunosuppressive CD4 + Foxp3 regulatory T cells (T regs ), especially those present in the microenvironment, as initially reported us. There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses. Furthermore, a broad spectrum human cancers also expresses TNFR2, while its expression normal tissue very limited. We thus hypothesized may be harnessed for tumor-targeted delivery chemotherapeutic agents. In this study, we performed proof-of-concept study constructing TNFR2-targeted PEGylated poly( dl -lactic-co-glycolic acid) (PLGA-PEG) nanodrug system [designated TNFR2-PLGA-ADR (Adriamycin)]. The results vitro showed had properties cellular binding and cytotoxicity toward mouse colon cancer cells. Further, upon intravenous injection, could efficiently accumulate MC38 CT26 tissues bind with tumor-infiltrating . Compared ADR ISO-PLGA-ADR, vivo effect was enhanced, which associated decrease an increase IFNγ CD8 cytotoxic lymphocytes tissue. Therefore, our clearly show promising strategy designing tumor-specific chemoimmunotherapeutic agent system.

Язык: Английский

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The Cullin-RING Ligase Family in Immune Regulation

Advances in experimental medicine and biology, Год журнала: 2024, Номер unknown, С. 81 - 87

Опубликована: Янв. 1, 2024

Язык: Английский

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促凋亡蛋白质Bim调控Treg细胞的免疫抑制功能

Journal of Zhejiang University SCIENCE B, Год журнала: 2023, Номер 24(12), С. 1180 - 1184

Опубликована: Дек. 1, 2023

Язык: Английский

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