ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs DOI

Zhiyuan Xiang,

Guixue Hou, Shanliang Zheng

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(37)

Published: Sept. 3, 2024

Proteostasis and genomic integrity are respectively regulated by the endoplasmic reticulum-associated protein degradation (ERAD) DNA damage repair signaling pathways, with both pathways essential for carcinogenesis drug resistance. How these coordinate each other remains unexplored. We found that ER stress specifically induces DNA-PKcs-regulated nonhomologous end joining (NHEJ) pathway to amend impede cell death. Intriguingly, sustained rapidly decreased activity of DNA-PKcs accumulated, facilitating a switch from adaptation This inactivation was caused increased KU70/KU80 degradation. Unexpectedly, ERAD ligase HRD1 efficiently destabilize classic nuclear HDAC1 in cytoplasm, catalyzing HDAC1's polyubiquitination at lysine 74, late stage stress. By abolishing HDAC1-mediated deacetylation, transmits signals nucleus. The resulting enhanced acetylation provides binding sites E3 TRIM25, promotion proteins. Both vitro vivo cancer models showed genetic or pharmacological inhibition HADC1 sensitizes colon cells inducers, including Food Drug Administration-approved celecoxib. antitumor effects combined approach were also observed patient-derived xenograft models. These findings identify mechanistic link between cytoplasm nucleus, indicating anticancer strategies may be developed induce severe while simultaneously inhibiting KU70/KU80/DNA-PKcs-mediated NHEJ signaling.

Language: Английский

Fundamentals of redox regulation in biology DOI
Helmut Sies, Ryan J. Mailloux,

Ursula Jakob

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 701 - 719

Published: April 30, 2024

Language: Английский

Citations

117
Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair DOI Creative Commons
Maja Radulovic, Eva M. Wenzel, Sania Gilani

et al.

The EMBO Journal, Journal Year: 2022, Volume and Issue: 41(24)

Published: Nov. 21, 2022

Abstract Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism repair that activated independently of recruitment. Lipidomic analyses showed increases lysosomal phosphatidylserine cholesterol after damage. Electron microscopy demonstrated membrane damage rapidly followed formation contacts with endoplasmic reticulum (ER), which depends on ER proteins VAPA/B. The cholesterol‐binding protein ORP1L was recruited to damaged lysosomes, accompanied accumulation a required VAP–ORP1L interactions. PtdIns 4‐kinase PI4K2A produced PtdIns4P lysosomes upon damage, knockout inhibited damage‐induced led failure repair. cholesterol–PtdIns4P transporter OSBP also its depletion caused resulted death. We conclude parallel ESCRTs provide lipids repair, generation removal central this response.

Language: Английский

Citations

96
Mechanisms and functions of protein S-acylation DOI
Francisco S. Mesquita, Laurence Abrami, Maurine E. Linder

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(6), P. 488 - 509

Published: Feb. 14, 2024

Language: Английский

Citations

53
Stay in touch with the endoplasmic reticulum DOI Open Access
Sha Sun,

Zhao Gan,

Mingkang Jia

et al.

Science China Life Sciences, Journal Year: 2024, Volume and Issue: 67(2), P. 230 - 257

Published: Jan. 4, 2024

Language: Английский

Citations

22
A single gene orchestrates androgen variation underlying male mating morphs in ruffs DOI
Jasmine L. Loveland, Alex Zemella, Vladimir Jovanović

et al.

Science, Journal Year: 2025, Volume and Issue: 387(6732), P. 406 - 412

Published: Jan. 23, 2025

Androgens are pleiotropic and play pivotal roles in the formation variation of sexual phenotypes. We show that differences circulating androgens between three male mating morphs ruff sandpipers linked to 17-beta hydroxysteroid dehydrogenase 2 (HSD17B2), encoded by a gene within supergene determines morphs. Low-testosterone males had higher HSD17B2 expression blood than high-testosterone males, as well brain areas related social behaviors testosterone production. Derived isozymes, which absent but preferentially expressed low-testosterone converted androstenedione faster ancestral isozyme. Thus, combination evolutionary changes regulation, sequence, structure single introduces endocrine underlying reproductive

Language: Английский

Citations

5
Enhancing drug penetration in solid tumors via nanomedicine: Evaluation models, strategies and perspectives DOI Creative Commons

Xiaoding Shen,

Dayi Pan, Qiyong Gong

et al.

Bioactive Materials, Journal Year: 2023, Volume and Issue: 32, P. 445 - 472

Published: Oct. 26, 2023

Effective tumor treatment depends on optimizing drug penetration and accumulation in tissue while minimizing systemic toxicity. Nanomedicine has emerged as a key solution that addresses the rapid clearance of free drugs, but achieving deep into solid tumors remains elusive. This review discusses various strategies to enhance penetration, including manipulation microenvironment, exploitation both external internal stimuli, pioneering nanocarrier surface engineering, development innovative tactics for active penetration. One outstanding strategy is organelle-affinitive transfer, which exploits unique properties specific cell organelles heralds potentially transformative approach transcellular transfer Rigorous models are essential evaluate efficacy these strategies. The patient-derived xenograft (PDX) model gaining traction bridge between laboratory discovery clinical application. However, journey from bench bedside nanomedicines fraught with challenges. Future efforts should prioritize deepening our understanding nanoparticle-tumor interactions, re-evaluating EPR effect, exploring novel nanoparticle transport mechanisms.

Language: Английский

Citations

40
Immune aging – A mechanism in autoimmune disease DOI Open Access
Yanyan Zheng, Qingxiang Liu, Jörg J. Goronzy

et al.

Seminars in Immunology, Journal Year: 2023, Volume and Issue: 69, P. 101814 - 101814

Published: Aug. 3, 2023

Language: Английский

Citations

35
Redox regulation of UPR signalling and mitochondrial ER contact sites DOI Creative Commons

Jose C. Casas-Martinez,

Afshin Samali, Brian McDonagh

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: June 7, 2024

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing exchange of material information, modulating calcium homeostasis, redox signalling, lipid transfer regulation mitochondrial dynamics. MERCS dynamic structures that allow cells to respond changes intracellular environment under normal homeostatic conditions, while their assembly/disassembly affected pathophysiological conditions such as ageing disease. Disruption protein folding lumen can activate Unfolded Protein Response (UPR), promoting remodelling membranes formation. The UPR stress receptor kinases PERK IRE1, located at or close MERCS. signalling be adaptive maladaptive, depending on whether disruption transient sustained. Adaptive via increase import, metabolism dynamics, maladaptive result excessive import activation apoptotic pathways. Targeting assembly an attractive therapeutic approach for range age-related neurodegeneration sarcopenia. This review highlights emerging evidence related role orchestrating inter-organelle communication mitochondria, ultimately determination function fate.

Language: Английский

Citations

10
Organelle‐Targeting Nanoparticles DOI Creative Commons

John Soukar,

Nicholas A. Peppas,

Akhilesh K. Gaharwar

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Organelles are specialized subunits within cells which carry out vital functions crucial to cellular survival and form a tightly regulated network. Dysfunctions in any of these organelles linked numerous diseases impacting virtually every organ system the human body. Targeted delivery therapeutics specific cell holds great promise for overcoming challenging improving treatment outcomes through minimization therapeutic dosage off‐target effects. Nanoparticles versatile effective tools organelles. offer several advantageous characteristics, including high surface area‐to‐volume ratio efficient loading ability attach targeting moieties (tethers) that enhance delivery. The choice nanoparticle shape, size, composition, properties, ligands depends on desired target organelle effect. Various platforms have been explored targeting, such as liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles. In this review, current emerging approaches design examined context various dysfunction. Specifically, advances therapies nucleus, mitochondria, lysosomes/endosomes, Golgi apparatus, endoplasmic reticulum comprehensively critically discussed.

Language: Английский

Citations

1
Baicalin inhibits LPS-induced apoptosis and inflammation in WI- 38 cells by promoting FOXA2/TRIM27 Interaction: Implications for pediatric pneumonia mechanisms DOI
Lihua Gao, Xianyi Zeng, Yubo Huang

et al.

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Language: Английский

Citations

1