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

---

Innate immune responses to RNA: sensing and signaling

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

Published: Jan. 25, 2024

Nucleic acids are among the most essential PAMPs (pathogen-associated molecular patterns). Animals have evolved numerous sensors to recognize nucleic and trigger immune signaling against pathogen replication, cellular stress cancer. Many sensor proteins (e.g., cGAS, AIM2, TLR9) signature of infection or responsible for innate response DNA. Remarkably, recent evidence demonstrates that cGAS-like receptors acquire ability sense RNA in some forms life. Compared with nucleic-acid sensing by responses based on various sensors, including RIG-I, MDA5, ADAR1, TLR3/7/8, OAS1, PKR, NLRP1/6, ZBP1, via a broad-spectrum axis. Importantly, new advances brought light potential clinical application targeting these pathways. Here, we highlight latest discoveries field. We also summarize activation regulatory mechanisms RNA-sensing signaling. In addition, discuss how is tightly controlled cells why disruption homeostasis linked disease.

Language: Английский

---

STUB1/CHIP: New insights in cancer and immunity

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115190 - 115190

Published: July 26, 2023

The STUB1 gene (STIP1 homology and U-box-containing protein 1), located at 16q13.3, encodes the CHIP (carboxyl terminus of Hsc70-interacting protein), an essential E3 ligase involved in quality control. comprises three domains: N-terminal tetratricopeptide repeat (TPR) domain, a middle coiled-coil C-terminal U-box domain. It functions as co-chaperone for heat shock (HSP) via TPR domain ligase, ubiquitinating substrates through its Numerous studies suggest that plays crucial role various physiological process, such aging, autophagy, bone remodeling. Moreover, emerging evidence has shown can degrade oncoproteins to exert tumor-suppressive functions, it recently emerged novel player tumor immunity. This review provides comprehensive overview STUB1's cancer, including clinical significance, impact on progression, dual roles, stem cell-like properties, angiogenesis, drug resistance, DNA repair. In addition, we explore immune cell differentiation maturation, inflammation, autoimmunity, antiviral response, Collectively, represents promising valuable therapeutic target cancer immunology.

Language: Английский

---

Improving the therapeutic efficacy of oncolytic viruses for cancer: targeting macrophages

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 22, 2023

Abstract Oncolytic viruses (OVs) for cancer treatment are in a rapid stage of development, and the direct tumor lysis activation comprehensive host immune response irreplaceable advantages immunotherapy. However, excessive antiviral responses also restrict spread OVs vivo infection cells. Macrophages functionally diverse innate cells that phagocytose present antigens to activate response, while limiting delivery tumors. Studies have shown functional propensity macrophages between affects overall therapeutic effect oncolytic virotherapy. How effectively avoid restrictive on reshape function tumor-associated virotherapy is an important challenge we now facing. Here, review summarize complex dual role virotherapy, highlighting how characteristics macrophage plasticity can be utilized cooperate with enhance anti-tumor effects, as well importance designing optimizing modalities future.

Language: Английский

---

ACADM inhibits AMPK activation to modulate PEDV-induced lipophagy and β-oxidation for impairing viral replication

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(8), P. 107549 - 107549

Published: July 11, 2024

Language: Английский

---

Viral infection and spread are inhibited by the polyubiquitination and downregulation of TRPV2 channel by the interferon-stimulated gene TRIM21

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114095 - 114095

Published: April 1, 2024

Interferon (IFN) contributes to the host's antiviral response by inducing IFN-stimulated genes (ISGs). However, their functional targets and mechanism of action remain elusive. Here, we report that one such ISG, TRIM21, interacts with degrades TRPV2 channel in myeloid cells, reducing its expression providing host protection against viral infections. Moreover, infection upregulates TRIM21 paracrine autocrine manners, downregulating neighboring cells prevent spread uninfected cells. Consistently, Trim21

Language: Английский

---

Friend or foe of tripartite motif-containing protein 21 in cardiovascular disease: A review

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142682 - 142682

Published: March 1, 2025

Language: Английский

---

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

---

TRIM21 Promotes Rabies Virus Production by Degrading IRF7 through Ubiquitination

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10892 - 10892

Published: June 30, 2023

Rabies, a highly fatal zoonotic disease, is significant global public health threat. Currently, the pathogenic mechanism of rabies has not been fully elucidated, and no effective treatment for available. Increasing evidence shows that tripartite-motif protein (TRIM) family proteins participates in host’s regulation viral replication. Studies have demonstrated upregulated expression 21 (TRIM21) brain tissue mice infected with virus. Related studies shown TRIM21 knockdown inhibits RABV replication, while overexpression exerted opposite effect. Knockdown interferon-alpha interferon-beta modulates inhibition replication caused by promotes Furthermore, our previous study revealed regulates secretion type I interferon during infection targeting regulatory factor 7 (IRF7). IRF7 reduced promoted via IRF7-IFN axis. Our identified as novel host required Thus, potential target or management.

Language: Английский

---

Roles of TRIM21/Ro52 in connective tissue disease-associated interstitial lung diseases

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

Published: Aug. 6, 2024

Multiple factors contribute to the development of connective tissue diseases (CTD), often alongside a range interstitial lung (ILD), including Sjögren's syndrome-associated ILD, systemic sclerosis-associated lupus erythematosus-associated idiopathic inflammatory myositis-associated ILD. TRIM21(or Ro52), an E3 ubiquitin ligase, plays vital role in managing innate and adaptive immunity, maintaining cellular homeostasis, is focal target for autoantibodies various rheumatic autoimmune diseases. However, effectiveness anti-TRIM21 antibodies diagnosing CTD remains matter debate because their non-specific nature. Recent studies indicate that TRIM21 its autoantibody are involved pathogenesis CTD-ILD play important diagnosis prognosis. In this review, we focus on contribution CTD-ILD, as well potential diagnostic value different types disease progression novel therapeutic target.

Language: Английский

---