Ubiquitination Insight from Spinal Muscular Atrophy—From Pathogenesis to Therapy: A Muscle Perspective DOI Open Access
Alfonso Bolado‐Carrancio, O. Tapia, José C. Rodríguez‐Rey

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8800 - 8800

Published: Aug. 13, 2024

Spinal muscular atrophy (SMA) is one of the most frequent causes death in childhood. The disease’s molecular basis deletion or mutations SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there spinal degeneration and large increase muscle atrophy, ubiquitin–proteasome system (UPS) plays significant role. In humans, paralogue SMN1, SMN2 encodes truncated SMNΔ7. Structural differences between SMN SMNΔ7 affect interaction proteins with UPS decrease stability protein. loss affects general ubiquitination process by lowering levels UBA1, main enzymes process. We discuss how both process, involved could be used as future targets for SMA treatment.

Language: Английский

Ubiquitin—A structural perspective DOI
Rashmi Agrata, David Komander

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 323 - 346

Published: Jan. 1, 2025

Language: Английский

Citations

3
The role of ubiquitination in health and disease DOI Creative Commons

Yan Liao,

Wangzheqi Zhang,

Yang Liu

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(10)

Published: Sept. 25, 2024

Ubiquitination is an enzymatic process characterized by the covalent attachment of ubiquitin to target proteins, thereby modulating their degradation, transportation, and signal transduction. By precisely regulating protein quality quantity, ubiquitination essential for maintaining homeostasis, DNA repair, cell cycle regulation, immune responses. Nevertheless, diversity enzymes extensive involvement in numerous biological processes contribute complexity variety diseases resulting from dysregulation. The relies on a sophisticated system, domains, receptors, which collectively impart versatility pathway. widespread presence highlights its potential induce pathological conditions. Ubiquitinated proteins are predominantly degraded through proteasomal also plays key role localization transport, as well inflammatory pathways. This review systematically delineates roles genomic stability, cellular proliferation, Furthermore, mechanisms implicated various pathologies, alongside current modulators discussed. Enhancing our comprehension aims provide novel insights into involving propose innovative therapeutic strategies clinical

Language: Английский

Citations

8
Genetic Code Expansion Approaches to Decipher the Ubiquitin Code DOI Creative Commons

Vera Wanka,

Maximilian Fottner, Marko Cigler

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(20), P. 11544 - 11584

Published: Sept. 23, 2024

The covalent attachment of Ub (ubiquitin) to target proteins (ubiquitylation) represents one the most versatile PTMs (post-translational modifications) in eukaryotic cells. Substrate modifications range from a single moiety being attached protein complex chains that can also contain Ubls (Ub-like proteins). Ubiquitylation plays pivotal roles aspects biology, and cells dedicate an orchestrated arsenal enzymes install, translate, reverse these modifications. entirety this system is coined code. Deciphering code challenging due difficulty reconstituting enzymatic machineries generating defined Ub/Ubl-protein conjugates. This Review provides comprehensive overview recent advances using GCE (genetic expansion) techniques study We highlight strategies site-specifically ubiquitylate discuss their advantages disadvantages, as well various applications. Additionally, we review potential small chemical targeting Ub/Ubls present GCE-based approaches additional layer complexity. Furthermore, explore methods rely on develop tools probe interactors offer insights into how future could help unravel complexity

Language: Английский

Citations

4
UBR5 in Tumor Biology: Exploring Mechanisms of Immune Regulation and Possible Therapeutic Implications in MPNST DOI Open Access
Diana Odhiambo, Shuangyi Fan, Angela C. Hirbe

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 161 - 161

Published: Jan. 7, 2025

Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), five-year survival rate at 20-50%, recurrence occurring up 50% individuals. For patients metastatic and unresectable disease, current options include cytotoxic chemotherapy, which offers minimal benefit, most die within five years diagnosis. Despite advances targeted therapy focusing on inhibiting Ras signaling its downstream effectors, clinical trials report highlighting need explore alternative pathways MPNST pathogenesis. Here, we discuss role E3 ubiquitin ligase, UBR5, cancer progression immune modulation across various malignancies, including breast, lung, ovarian cancer. We focus mechanisms UBR5 contributes tumorigenesis, influence microenvironment modulation. Additionally, UBR5's roles normal tissue function, DNA damage response, metastasis, therapeutic resistance, illustrating multifaceted contribution biology. evidence implicating evasion highlight potential as target enhance efficacy checkpoint blockade (ICB) MPNST, typically an cold microenvironment. outline immune-based strategies challenges management, ongoing efforts shift landscape ultimately, suggest that targeting could be novel strategy potentiate ICB therapy-mediated anti-tumor outcomes, particularly inoperable or disease.

Language: Английский

Citations

0
Dysregulation of deubiquitinylases: a linchpin of gastrointestinal diseases DOI Creative Commons

Lorena Ferino,

Michael Naumann

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Primary disorders of polyubiquitination: Dual roles in autoinflammation and immunodeficiency DOI
András N. Spaan, Bertrand Boisson, Seth L. Masters

et al.

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(5)

Published: April 15, 2025

The last decades have brought a rapid expansion of the number primary disorders related to polyubiquitination pathways in humans. Most these manifest with two seemingly contradictory clinical phenotypes: autoinflammation, immunodeficiency, or both. We provide an overview molecular pathogenesis disorders, and their role inflammation infection. By focusing on data from human genetic diseases, we explore complexities corresponding phenotypes deficiencies. offer road map for discovery new etiologies. considering triggers that induce inflammation, propose autoinflammation immunodeficiency as continuous phenotypes.

Language: Английский

Citations

0
Regulation of Mitochondria-Derived Immune Activation by ‘Antiviral’ TRIM Proteins DOI Creative Commons
Seeun Oh, Michael A. Mandell

Viruses, Journal Year: 2024, Volume and Issue: 16(7), P. 1161 - 1161

Published: July 19, 2024

Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered release immune-stimulatory molecules boost interferon production. These same released by damaged induce pathogenic, antiviral-like immune in absence infection. This review explores how members tripartite motif-containing (TRIM) protein family, which recognized their roles defense, regulate mitochondria-based activation. TRIMs essential components signal transduction pathways function directly acting restriction factors. carry out conceptually similar activities when controlling related mitochondria. First, they modulate activated mitochondrial molecules. Second, co-ordinate direct removal associated immune-activating factors through mitophagy. insights broaden scope TRIM actions immunity may implicate diseases with mitochondria-derived inflammation.

Language: Английский

Citations

3
Critical Analysis of Cytoplasmic Progression of Inflammatory Signaling Suggests Potential Pharmacologic Targets for Wound Healing and Fibrotic Disorders DOI Creative Commons
Michael L. Samulevich, Liam E. Carman, Brian J. Aneskievich

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(12), P. 2723 - 2723

Published: Nov. 28, 2024

Successful skin wound healing is dependent on an interplay between epidermal keratinocytes and dermal fibroblasts as they react to local extracellular factors (DAMPs, PAMPs, cytokines, etc.) surveyed from that environment by numerous membrane receptors (e.g., TLRs, cytokine receptors, etc.). In turn, those are the start of a cytoplasmic signaling pathway where balance key effective and, needed, cell matrix regeneration. When directed through NF-κB, these routes lead transient responses benefit initiating immune recruitment, replication, chemokine production, protein synthesis. The converse can also occur, ongoing canonical NF-κB activation leads chronic, hyper-responsive states. Here, we assess three players, TAK1, TNFAIP3, TNIP1, in regulation activation, which, because their distinctive yet inter-related functions, either promote or limit activation. Their balanced function integral successful healing, given significant control over expression inflammation-, fibrosis-, remodeling-associated genes. Intriguingly, proteins have been emphasized dysregulated central systemic sclerosis (SSc). Notably, diffuse SSc shares some tissue features similar excessive inflammatory/fibrotic response without eventual resolution. Taking cue certain instances aberrant having shared aspects, e.g., chronic inflammation fibrosis, this review looks for first time, our knowledge, at what pathologies might common regarding progression NF-κB-mediated signaling. Additionally, while TNIP1 often investigated reported individually, propose them here whose consequences very highly interconnected focus NF-κB. We thus highlight emerging promise clinical derived improved understanding signal modulators. Depending protein, its indirect direct pharmacological has reported. Current findings support further intensive studies points both basic healthy cells well with goal targeting translational multiple cutaneous situations, whether stemming acute injury response.

Language: Английский

Citations

2
Structural diversity of the CE-clan proteases in bacteria to disarm host ubiquitin defenses DOI Creative Commons
Lucía Sánchez-Alba, Helena Borràs-Gas, Ge Huang

et al.

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

1
Ubiquitination Insight from Spinal Muscular Atrophy—From Pathogenesis to Therapy: A Muscle Perspective DOI Open Access
Alfonso Bolado‐Carrancio, O. Tapia, José C. Rodríguez‐Rey

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8800 - 8800

Published: Aug. 13, 2024

Spinal muscular atrophy (SMA) is one of the most frequent causes death in childhood. The disease’s molecular basis deletion or mutations SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there spinal degeneration and large increase muscle atrophy, ubiquitin–proteasome system (UPS) plays significant role. In humans, paralogue SMN1, SMN2 encodes truncated SMNΔ7. Structural differences between SMN SMNΔ7 affect interaction proteins with UPS decrease stability protein. loss affects general ubiquitination process by lowering levels UBA1, main enzymes process. We discuss how both process, involved could be used as future targets for SMA treatment.

Language: Английский

Citations

0