Targeting PPARγ via SIAH1/2-mediated ubiquitin-proteasomal degradation as a new therapeutic approach in luminal-type bladder cancer DOI Creative Commons

Chih-Chieh Tu,

Tsung‐Han Hsieh, Cheng‐Ying Chu

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(12)

Published: Dec. 18, 2024

Bladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Despite recent approvals of immune checkpoint inhibitors and targeted therapy for muscle invasive or recurrent BC, options remain limited patients with non-muscle BC (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) chemotherapy. NMIBC more frequently classified as a luminal subtype, in which increased PPARγ activity key feature promoting tumor growth evasion immunosurveillance. Cinobufotalin one major compound bufadienolides, primary active components toad venom that has been utilized clinical treatment cancer. We herein focused on cinobufotalin, examining its anticancer molecular mechanisms luminal-type NMIBC. Our results newly reveal cinobufotalin strongly suppresses viability proliferation cells minimal cytotoxic effects normal uroepithelial cells, exhibits significant antitumor RT112 xenograft model. Mechanistically, our sub-G1-phase cell accumulation, Annexin V staining, caspase-3/8/9 activation, PARP activation analyses show induces apoptosis cells. significantly inhibited levels downstream targets, well lipid droplet formation free fatty acid overexpression rescued from cinobufotalin-induced mitigated downregulation FASN PLIN4. Finally, we seemingly first time promotes SIAH1/2-mediated proteasomal degradation Together, these findings compellingly support idea could be developed promising therapeutic agent treating

Language: Английский

Characteristics of the Kelch domain containing (KLHDC) subfamily and relationships with diseases DOI Creative Commons
Courtney Pilcher,

Paula Armina V. Buco,

Jia Q. Truong

et al.

FEBS Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

The Kelch protein superfamily is an evolutionary conserved family containing 63 alternate coding members. split into three subfamilies: like (KLHL), Kelch‐repeat and bric‐a‐bracs (BTB) domain (KBTBD) (KLHDC). KLHDC subfamily one of the smallest within superfamily, 10 primary There little known about structures functions subfamily; however, they are thought to be involved in several cellular molecular processes. Recently, there have been significant structural biochemical advances for KLHDC2, which has aided our understanding other Furthermore, small molecules directly targeting KLHDC2 identified, act as tools targeted degradation. This review utilises this information, conjunction with a thorough exploration aspects potential biological summarise relationship between KLHDCs human disease.

Language: Английский

Citations

2
Mechanisms and Therapeutic Strategies for NLRP3 Degradation via Post-Translational Modifications in Ubiquitin-proteasome and Autophagy Lysosomal Pathway DOI

Kaiyue Su,

Minghai Tang, Jie Wu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117476 - 117476

Published: March 4, 2025

Language: Английский

Citations

1
Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders and cancer DOI
Aastha Kaushik,

Somya Parashar,

Rashmi K. Ambasta

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102279 - 102279

Published: March 22, 2024

Language: Английский

Citations

8
Application of DELs for E3 Ligase Ligand Discovery and Targeted Protein Degradation DOI
Marie L. Malone,

Nicholas A. Sanchez,

Shimin Hu

et al.

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 134 - 156

Published: Feb. 21, 2025

Targeted protein degradation (TPD) provides new therapeutic opportunities beyond traditional inhibitors. TPD relies on the ability to induce proximity between an E3 ligase and target of interest, harnessing ubiquitin proteasome system ubiquitylate degrade target. This can be induced by either monofunctional ligands (molecular glues) or bifunctional molecules that tether ligases together. DNA encoded libraries (DELs) provide rapid access diverse chemical space for ligand discovery and, their design, facilitate development both molecular glues degraders.

Language: Английский

Citations

0
The Dual Nature of KLHL Proteins: From Cellular Regulators to Disease Drivers DOI Creative Commons

Verdiana Di Giulio,

Angelo Canciello,

Erminia Carletti

et al.

European Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 104(2), P. 151483 - 151483

Published: March 14, 2025

Language: Английский

Citations

0
E3 ubiquitin ligases and their therapeutic potential in disease Management DOI
Geet Madhukar, Md Azizul Haque, Shawez Khan

et al.

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116875 - 116875

Published: March 1, 2025

Language: Английский

Citations

0
Protein Ligases: Nature’s Gift for Protein/Peptide Synthesis DOI Creative Commons

Yvonne Ritsema,

H. Li,

Qingfei Zheng

et al.

BioChem, Journal Year: 2025, Volume and Issue: 5(2), P. 11 - 11

Published: May 7, 2025

Proteins are structurally and functionally diverse biomacromolecules that serve a variety of essential activities to ensure complex biological homeostasis. The desire elucidate enhance these functions has been at the forefront research for many decades. However, generating active proteins via recombinant expression or through chemical total synthesis each limitations in terms yield functionality. Nature provided solution this problem evolving protein ligases catalyze formation amide bonds between peptides/proteins, which can be exploited by engineers develop robust functional proteins. Here, we summarize biochemical mechanisms applications multiple cysteine-based ligases, especially focusing on how they have utilized therapeutics engineering, as well inspired chemists efficient methodologies (e.g., native ligation).

Language: Английский

Citations

0
E3 ubiquitin ligase ANKIB1 attenuates antiviral immune responses by promoting K48-linked polyubiquitination of MAVS DOI Creative Commons
Wei Liu,

Cui Yuan,

Buwen Fu

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114687 - 114687

Published: Aug. 30, 2024

Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with mitochondrial antiviral signaling proteins (MAVSs) to activate IRF3 and nuclear factor κB (NF-κB) signaling, initiating innate immune responses. Thus, RLR activation plays a vital role in the removal of invasive RNA viruses while maintaining homeostasis. However, inadequate or excessive immunity can cause harm even lead lethal consequences. In this study, we identify an E3 ligase, ankyrin repeat IBR domain containing 1 (ANKIB1), which suppresses via MAVS. ANKIB1 binds MAVS enhance K48-linked polyubiquitination K311R, causing proteasomal degradation Deficiency significantly increases RLR-mediated production type I interferon (IFN) along pro-inflammatory factors. Consequently, deficiency remarkably decreases replication vivo. Therefore, reveal that restricts RLR-induced activation, indicating its potential as therapeutic target for infections.

Language: Английский

Citations

2
Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1 DOI Creative Commons
Yan Zeng, Man Guo, Qi Wu

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one how specific gut-derived affect progression DKD remain largely unknown.

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