Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs DOI Creative Commons
Jindr̂ich Sedláĉek

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 8(1), P. 21 - 35

Published: Dec. 16, 2024

The 26S proteasome degrades the majority of cellular proteins and affects all aspects life. Therefore, abundance, proper assembly, activity in different life contexts need to be precisely controlled. Impaired is considered a causative factor several serious disorders. Recent advances biology have revealed that can activated by factors or small molecules. Thus, ubiquitin-dependent degradation has effects such as extending lifespan models, preventing accumulation protein aggregates, reducing their negative impact on cells. Increased proteasome-mediated reduces proteotoxic stress potentially improve efficacy engineered degraders, PROTACs, particularly situations characterized malfunction. Here, emerging ideas recent insights into pharmacological activation at transcriptional posttranslational levels are summarized.

Language: Английский

Proteasome Inhibition Enhances Lysosome-mediated Targeted Protein Degradation DOI Open Access
Ahmed M. Elshazly, Nayyerehalsadat Hosseini, Shanwei Shen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

ABSTRACT Proteasome inhibitor drugs are currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. These inhibitors cause accumulation of undegraded proteins, thus inducing proteotoxic stress consequent death. However, cancer cells counteract this effect by activating an adaptive response through transcription factor Nuclear erythroid 2-related 1 (NRF1, also known as NFE2L1). NRF1 induces transcriptional upregulation proteasome autophagy/lysosomal genes, thereby reducing diminishing effectiveness inhibition. While suppressing protective autophagy is one potential strategy, here we investigated whether heightened could instead be leveraged therapeutically. To end, designed autophagy-targeting chimera (AUTAC) compound selectively degrade anti-apoptotic protein Mcl1 via lysosome. Our results show that lysosome-mediated targeted degradation significantly amplified presence inhibition, a NRF1-dependent manner. The combination carfilzomib AUTAC synergistically promoted death both wild-type inhibitor-resistant lung cells. Thus, our work offers novel strategy for enhancing efficacy exploiting response. More broadly, study establishes framework amplifying degradation, with applications therapeutics beyond.

Language: Английский

Citations

0
Deletion of Nrf1α exacerbates oxidative stress-induced cellular senescence by disrupting cell homeostasis DOI

Da Lyu,

Meng Wang, Lu Qiu

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: unknown, P. 119970 - 119970

Published: April 1, 2025

Language: Английский

Citations

0
NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome DOI Creative Commons
Hossein Khodadadi,

Kamila Łuczyńska,

Dawid Winiarczyk

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: May 1, 2025

Maintaining proteostasis is critical for neuronal health, with its disruption underpinning the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Nuclear Factor Erythroid 2-Related 1 (NFE2L1) has emerged a key regulator proteostasis, integrating proteasome function, autophagy, ferroptosis to counteract oxidative stress protein misfolding. This review synthesizes current knowledge on role NFE2L1 in maintaining homeostasis, focusing mechanisms mitigating proteotoxic supporting cellular offering protection against neurodegeneration. Furthermore, we discuss pathological implications dysfunction explore potential therapeutic target. By highlighting gaps understanding presenting future research directions, this aims elucidate NFE2L1's advancing treatment strategies

Language: Английский

Citations

0
Small-molecule activators of NRF1 transcriptional activity prevent protein aggregation DOI
Jindr̂ich Sedláĉek,

Zuzana Smahelova,

Michael Adamek

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 183, P. 117864 - 117864

Published: Jan. 29, 2025

Language: Английский

Citations

0
Increased Oxidative Stress and Autophagy in NGLY1 Patient iPSC-derived Neural Stem Cells DOI Creative Commons
Zeenat A. Shyr,

Soukaina Amniouel,

Kofi Owusu-Ansah

et al.

Experimental Cell Research, Journal Year: 2025, Volume and Issue: unknown, P. 114540 - 114540

Published: April 1, 2025

NGLY1 (N-glycanase) is a de-glycosylating enzyme that promotes clearance of misfolded glycan proteins. deficiency leads to disease pathology with varied symptoms, including severe neurological defects. There are no therapeutic options currently available for the treatment this rare disease. With goal finding potential avenues, we performed comprehensive characterization aberrant cellular stress pathways in patient relevant model deficiency. For more accurate study without other confounding factors, compared differences between iPSC-derived neural stem cells carrying commonly occurring nonsense mutation c.1201A>T (p.R401X) and their genetically similar CRISPR-corrected isogenic controls. Our findings demonstrate an upregulation ER stress, increased autophagic flux significant signs oxidative stress. These results provide new insights into dysfunctions associated disorder. Moreover, they point better establishing reliable high throughput phenotypic assays can be utilized drug discovery.

Language: Английский

Citations

0
Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma DOI Creative Commons
Jindr̂ich Sedláĉek

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: May 26, 2025

Language: Английский

Citations

0
Biologic activity and treatment resistance to gastrointestinal cancer: the role of circular RNA in autophagy regulation DOI Creative Commons
Bo Zhang, Zhe Li,

Guoliang Ye

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Aug. 30, 2024

Circular RNAs (circRNAs) lack the 5'-end methylated guanine cap structure and 3' polyadenylate tail structure, classifying it as a non-coding RNA. With extensive investigation of circRNA, its role in regulating cell death has garnered significant attention recent years, establishing recognized participant cancer's biological processes. Autophagy, an essential pathway programmed (PCD), involves formation autophagosomes using lysosomes to degrade cellular contents under regulation various autophagy-related (ATG) genes. Numerous studies have demonstrated that circRNA can modulate activity cancer cells by influencing autophagy pathway, exhibiting dualistic suppressing or promoting carcinogenesis. In this review, we comprehensively analyze how impacts progression gastrointestinal (GIC). Additionally, discuss drug resistance phenomena associated with GIC. This review offers valuable insights into exploring potential targets for prognosis treatment strategies related

Language: Английский

Citations

1
Deletion of Nrf1 exacerbates oxidative stress-induced cellular senescence by disrupting the cell homeostasis DOI Open Access

Da Lyu,

Meng Wang, Lu Qiu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 9, 2024

Abstract Cellular senescence has been accepted as a fundamental contributor to ageing and variety of age-related diseases, in which oxidative stress further recognized play critical initiation role. However, the anti-senescence potential antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by Nfe2l1 ) remains elusive date, even though hitherto accumulating evidence demonstrates that it is an indispensable redox-determining transcription for maintaining cellular homeostasis organ integrity. Herein, we discovered deletion Nrf1 resulted markedly elevated characteristics Nrf1α −/− cells, characterized two distinct experimental models induced stress, are evinced typically heightened activity senescence-associated β-galactosidase progressive secretory phenotype (SASP), along with decreased cell vitality intensified cycle arrest. Further investigation also uncovered such acceleration stress-induced from disturbance homeostasis, because deficiency leads STAG2- SMC3-dependent chromosomal stability disruption autophagy dysfunction, accompanied excessive accumulation Nrf2 (encoded Nfe2l2 ). The aberrant hyperactive cannot effectively counteract escalating caused . Overall, this study provided series supporting indeed exerts essential protective function against senescence, thereby, highlighting its primary contribution robust homeostasis.

Language: Английский

Citations

0
Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs DOI Creative Commons
Jindr̂ich Sedláĉek

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 8(1), P. 21 - 35

Published: Dec. 16, 2024

The 26S proteasome degrades the majority of cellular proteins and affects all aspects life. Therefore, abundance, proper assembly, activity in different life contexts need to be precisely controlled. Impaired is considered a causative factor several serious disorders. Recent advances biology have revealed that can activated by factors or small molecules. Thus, ubiquitin-dependent degradation has effects such as extending lifespan models, preventing accumulation protein aggregates, reducing their negative impact on cells. Increased proteasome-mediated reduces proteotoxic stress potentially improve efficacy engineered degraders, PROTACs, particularly situations characterized malfunction. Here, emerging ideas recent insights into pharmacological activation at transcriptional posttranslational levels are summarized.

Language: Английский

Citations

0