Multiple unfolded protein response pathways cooperate to link cytosolic dsDNA release to stimulator of interferon gene activation DOI Creative Commons

Tiancheng Hu,

Yiping Liu,

Jeremy Fleck

et al.

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

Published: July 19, 2024

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to “sterile” endogenous threats and pathogens without nominal or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought determine if ER generated a ligand, identify UPR pathways involved. Induction of IFN-β expression following stimulation with inducer thapsigargin (TPG) oxygen glucose deprivation required both dsDNA-sensing GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, immunofluorescence visualized dsDNA punctae murine human cells, providing cGAS stimulus. N-acetylcysteine decreased induction by TPG, implicating reactive species (ROS). However, mitoTEMPO, oxidative inhibitor did not impact TPG-induced IFN. On other hand, inhibiting inositol requiring enzyme 1 (IRE1) its target transcription factor XBP1 generation dsDNA. iNOS upregulation was XBP1-dependent, IFN-β, ROS downstream IRE1-XBP1 pathway. Inhibition PKR-like kinase (PERK) pathway also attenuated cytoplasmic release. PERK-regulated apoptotic Bim for release mRNA induction. Finally, PERK contributed IFN-induction RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that stressors, including viral ligands such viruses, trigger multiple canonical cooperate activate via

Language: Английский

Genetic and pharmacological targeting of XBP1 alleviates hepatic ischemia reperfusion injury by enhancing FoxO1-dependent mitophagy DOI

Baicheng Kuang,

Mengqin Wang, Hao Yan

et al.

Translational research, Journal Year: 2024, Volume and Issue: 272, P. 162 - 176

Published: March 15, 2024

Language: Английский

Citations

4
The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson’s disease DOI Creative Commons
Lijun Dai, Jiannan Wang, Lanxia Meng

et al.

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(2), P. e3002974 - e3002974

Published: Feb. 18, 2025

Parkinson’s disease (PD) is a neurodegenerative characterized by the death of dopaminergic neurons in substantia nigra and formation Lewy bodies that are composed aggregated α-synuclein (α-Syn). However, factors regulate α-Syn pathology nigrostriatal degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), brain-specific oxysterol catalyzed CYP46A1, elevated cerebrospinal fluid PD patients. Herein, we show levels CYP46A1 24-OHC patients increase with age mouse model. Overexpression intensifies pathology, whereas genetic removal attenuates neurotoxicity brain. supplementation exogenous exacerbates mitochondrial dysfunction induced fibrils. Intracerebral injection enhances spread neurodegeneration via X-box binding protein 1 (XBP1) lymphocyte-activation gene 3 (LAG3) levels. Thus, promote XBP1–LAG3 axis. Strategies aimed at inhibiting CYP46A1-24-OHC axis LAG3 could hold promise as disease-modifying therapies

Language: Английский

Citations

0
Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart DOI Open Access

Sakthijothi Muthu,

Zinnia Tran,

Jayapalraja Thilagavathi

et al.

The Journal of Cardiovascular Aging, Journal Year: 2025, Volume and Issue: 5(1)

Published: Feb. 18, 2025

Introduction: Aging is a multifaceted biological process characterized by progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system contributes to onset of diseases. The mitochondria (mt) endoplasmic reticulum (ER) play synergistic roles maintaining homeostasis energy production heart. Nevertheless, their response cardiac aging not well known. Aim: This study explores mt ER stress responses associated factors, such as metabolic, cellular, autophagic stress, aging. Methods Results: We utilized 10- 25-month-old CBA/CaJ mice evaluate mt, ER, responses. studied gene expression for mitochondrial biogenesis, response, autophagy metabolic markers, activating transcription factors that mediate found no significant difference mtDNA content mRNA factor, Tfam ; however, selective genes, mt-Cytb mt-Co2, showed induction 25-month-aged compared 10-month-young hearts. Interestingly, genes several proteases components, including Lonp1, Yme1l1, Afg3l2, Spg7 , were induced, with substantial Clpp Clpx . However, age-associated differences observed chaperones (Hspa9 Hspd1 ), but Dnaja2 co-chaperone, was observed. Xbp1 Atf6 markedly induced aged hearts, accompanied decreased chaperone Hsp90b change Hspa5 Dnajb9 chaperones. Dnm1l significant, whereas Mfn1 Fis1 downregulated contrast Mfn2 suggesting dysregulated dynamics heart regulators Furthermore, hearts increased oxidative damage evidenced elevated lipid peroxidation (4-HNE) levels. Conclusion: These findings demonstrate triggers heart, which over time leads accumulation damage, causing impairment, highlighting these pathways potential therapeutic targets mitigating age-related dysfunction.

Language: Английский

Citations

0
Hippo pathway activated by circulating reactive oxygen species mediates cardiac diastolic dysfunction after acute kidney injury DOI
Xiao Han, Quan Hong, Fei Peng

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(5), P. 167184 - 167184

Published: April 21, 2024

Language: Английский

Citations

3
Endoplasmic reticulum stress signaling modulates ischemia/reperfusion injury in the aged heart by regulating mitochondrial maintenance DOI Creative Commons
Ji Zhang, Yuanyuan Zhao, Nianqiao Gong

et al.

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: July 23, 2024

Abstract Aging is associated with an increased risk of myocardial ischemia/reperfusion injury (IRI). With increasing prevalence cardiovascular diseases such as coronary arteriosclerosis in older people, there has been interest understanding the mechanisms IRI to develop therapeutics that can attenuate its damaging effects. Previous studies identified abnormal mitochondria, involved cellar senescence and oxidative stress, are master subcellular organelle induces IRI. In addition, endoplasmic reticulum (ER) stress also Cellular adaptation ER achieved by activation molecular chaperones folding enzymes, which provide important link between gene programs. this review, we outline how these stress-related molecules affect via crosstalk mitochondrial homeostasis discuss may offer promising novel therapeutic targets strategies against age-related diseases.

Language: Английский

Citations

2
Multiple Unfolded Protein Response pathways cooperate to link cytosolic dsDNA release to Stimulator of Interferon Gene (STING) activation DOI Open Access

Tiancheng Hu,

Yiping Liu,

Jeremy Fleck

et al.

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

Published: May 14, 2024

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought determine if ER generated a ligand, identify UPR pathways involved. Induction of IFN-β expression following stimulation with inducer thapsigargin (TPG) oxygen glucose deprivation required both dsDNA-sensing GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, immunofluorescence visualized dsDNA punctae murine human cells, providing cGAS stimulus. N-acetylcysteine decreased induction by TPG, implicating reactive species (ROS). However, mitoTEMPO, oxidative inhibitor did not impact TPG-induced IFN. On other hand, inhibiting inositol requiring enzyme 1 (IRE1) its target transcription factor XBP1 generation dsDNA. iNOS upregulation was XBP1-dependent, IFN-β, ROS downstream IRE1-XBP1 pathway. Inhibition PKR-like kinase (PERK) pathway also attenuated cytoplasmic release. PERK-regulated apoptotic Bim for release mRNA induction. Finally, PERK contributed IFN-induction RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that stressors, including viral ligands such viruses, trigger multiple canonical cooperate activate via

Language: Английский

Citations

0
Multiple unfolded protein response pathways cooperate to link cytosolic dsDNA release to stimulator of interferon gene activation DOI Creative Commons

Tiancheng Hu,

Yiping Liu,

Jeremy Fleck

et al.

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

Published: July 19, 2024

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to “sterile” endogenous threats and pathogens without nominal or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought determine if ER generated a ligand, identify UPR pathways involved. Induction of IFN-β expression following stimulation with inducer thapsigargin (TPG) oxygen glucose deprivation required both dsDNA-sensing GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, immunofluorescence visualized dsDNA punctae murine human cells, providing cGAS stimulus. N-acetylcysteine decreased induction by TPG, implicating reactive species (ROS). However, mitoTEMPO, oxidative inhibitor did not impact TPG-induced IFN. On other hand, inhibiting inositol requiring enzyme 1 (IRE1) its target transcription factor XBP1 generation dsDNA. iNOS upregulation was XBP1-dependent, IFN-β, ROS downstream IRE1-XBP1 pathway. Inhibition PKR-like kinase (PERK) pathway also attenuated cytoplasmic release. PERK-regulated apoptotic Bim for release mRNA induction. Finally, PERK contributed IFN-induction RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that stressors, including viral ligands such viruses, trigger multiple canonical cooperate activate via

Language: Английский

Citations

0