Cited by Ubiquitin and Ubiquitin‐Like Modifications in Organelle Stress Signaling: Ub, Ub, Ub, Ub, Stayin’ Alive, Stayin’ Alive

PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response DOI

Othman Abu Shelbayeh,

Tasnim Arroum, Silke Morris

et al.

Antioxidants, Journal Year: 2023, Volume and Issue: 12(5), P. 1075 - 1075

Published: May 10, 2023

Mitochondria play a major role in ROS production and defense during their life cycle. The transcriptional activator PGC-1α is key player the homeostasis of energy metabolism therefore closely linked to mitochondrial function. responds environmental intracellular conditions regulated by SIRT1/3, TFAM, AMPK, which are also important regulators biogenesis In this review, we highlight functions regulatory mechanisms within framework, with focus on its involvement lifecycle metabolism. As an example, show scavenging under inflammatory conditions. Interestingly, stress response factor NF-κB, regulates immune response, reciprocally regulated. During inflammation, NF-κB reduces expression activity. Low activity leads downregulation antioxidant target genes resulting oxidative stress. Additionally, low levels concomitant promote activity, exacerbates response.

Language: Английский

Citations

161

Mitochondria and cell death DOI

Hannah L. Glover, Annabell Schreiner, Grant Dewson

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(9), P. 1434 - 1446

Published: June 20, 2024

Language: Английский

Citations

Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response DOI

Esmee Vringer, Rosalie Heilig, Joel S. Riley

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(6), P. 904 - 930

Published: Feb. 9, 2024

Abstract Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown be inherently pro-inflammatory with emerging cellular roles, including its ability elicit anti-tumour immunity. Nonetheless, how triggers inflammation the regulates this remains poorly defined. We find upon MOMP, many proteins localised either inner or mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves recruit adaptor molecule NEMO, leading of NF-κB signalling. show disruption integrity through different means engagement similar signalling platform. Therefore, directly controls inflammation, such permeabilised mitochondria initiate

Language: Английский

Citations

Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling DOI

Olivia Harding, Elisabeth Holzer, Julia F. Riley

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(17), P. 3188 - 3204.e7

Published: Sept. 1, 2023

Failure to clear damaged mitochondria via mitophagy disrupts physiological function and may initiate damage signaling inflammatory cascades, although how these pathways intersect remains unclear. We discovered that nuclear factor kappa B (NF-κB) essential regulator NF-κB effector molecule (NEMO) is recruited in a Parkin-dependent manner time course similar recruitment of the structurally related adaptor, optineurin (OPTN). Upon recruitment, NEMO partitions into phase-separated condensates distinct from OPTN but colocalizing with p62/SQSTM1. turn, recruits active catalytic inhibitor kinase (IKK) component phospho-IKKβ, initiating upregulation cytokines. Consistent potential neuroinflammatory role, primary astrocytes upon oxidative stress. These findings suggest damaged, ubiquitinated serve as an intracellular platform innate immune signaling, promoting formation activated IKK complexes sufficient activate signaling. propose are initiated parallel response mitochondrial

Language: Английский

Citations

Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling DOI

Simran Goel, Rosario Oliva, Sadasivam Jeganathan�

et al.

Life Science Alliance, Journal Year: 2023, Volume and Issue: 6(4), P. e202201607 - e202201607

Published: Jan. 31, 2023

The NF-κB essential modulator NEMO is the core regulatory component of inhibitor κB kinase complex, which a critical checkpoint in canonical signaling downstream innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1β, binds linear M1-linked ubiquitin chains generated by LUBAC, promoting its oligomerization subsequent activation associated kinases. Here we show that M1-ubiquitin induce phase separation formation assemblies cells after exposure IL-1β. Phase promoted both binding covalent linkage but not sufficient for separation. Supporting functional relevance signaling, pathogenic mutant, impaired chains, does undergo defective mediating IL-1β-induced activation.

Language: Английский

Citations

Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival DOI

Laura Zein,

Marvin Dietrich,

Denise Balta

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 21

Published: Jan. 2, 2025

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of material. Maintenance lysosomal integrity is essential homeostasis membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes repaired or degraded via lysophagy, during which glycans, exposed on ruptured membranes, recognized by galectins leading to K48- K63-linked poly-ubiquitination (poly-Ub) proteins followed recruitment macroautophagic/autophagic machinery degradation. Linear (M1) poly-Ub, catalyzed linear ubiquitin chain assembly complex (LUBAC) E3 ligase removed OTULIN (OTU deubiquitinase with linkage specificity) exerts important functions in immune signaling survival, but role M1 poly-Ub remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged accumulate an OTULIN- K63 Ub-dependent manner. LMP-induced at damaged contributes lysosome degradation, recruits NFKB (nuclear factor kappa B) modulator IKBKG/NEMO locally activates inhibitor kinase (IKK) trigger activation. Inhibition enhances LMP- OTULIN-regulated death, indicating pro-survival LMP potentially lysophagy. Finally, also occurs primary mouse neurons induced pluripotent stem cell-derived human dopaminergic neurons. Our results reveal novel homeostasis, lysosomes, implications signaling, inflammation death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component nuclear B complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA protein 1-WD repeat FYVE containing 1; DGCs: degradative compartments; DIV: days vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting required transport; FBXO27: F-box 27; GBM: glioblastoma multiforme; IKBKB/IKKB: subunit beta; IKBKG/NEMO: regulatory gamma; IKK: kinase; iPSC: cell; KBTBD7: kelch BTB 7; KO: knockout; LAMP1: associated LCD: death; LGALS: galectin; LMP: permeabilization; LLOMe: ester; LOP: loperamide; LUBAC: LRSAM1: leucine rich sterile alpha motif MAP1LC3/LC3: microtubule 1 light 3; MTOR: mechanistic target rapamycin MTORC1: MTOR NBR1: NBR1 cargo receptor; NFKB/NF-κB: B; NFKBIA/IĸBα: polypeptide gene enhancer B-cells alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type C3HC4-type zinc finger RNF31/HOIP: ring 31; SHARPIN: SHANK RH interactor; SQSTM1/p62: sequestosome SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 TBK1: TANK TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A TRIM16: tripartite 16; Ub: ubiquitin; UBE2QL1: conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX 6; VCP/p97: valosin WIPI2: WD domain, phosphoinositide interacting YOD1: YOD1 deubiquitinase.

Language: Английский

Citations

NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62 DOI

Nikolas Furthmann, Verian Bader,

Lena Angersbach

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 19, 2023

Abstract NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of proteostasis by promoting autophagosomal clearance aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress are vulnerable to challenges. Moreover, patient with mutation the NEMO-encoding IKBKG gene resulting defective binding linear ubiquitin chains, developed widespread mixed brain proteinopathy, including α-synuclein, tau TDP-43 pathology. amplifies ubiquitylation at α-synuclein aggregates promotes local concentration p62 into foci. In vitro, lowers threshold concentrations required for ubiquitin-dependent phase transition p62. summary, reshapes aggregate surface efficient providing mobile interphase favoring co-condensation

Language: Английский

Citations

Mitochondria in Mesenchymal Stem Cells: Key to Fate Determination and Therapeutic Potential DOI

Yang Liu, Lingjuan Wang, Jihui Ai

et al.

Stem Cell Reviews and Reports, Journal Year: 2024, Volume and Issue: 20(3), P. 617 - 636

Published: Jan. 24, 2024

Language: Английский

Citations

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders DOI

George Anderson, Abbas F. Almulla, Russel J. Reıter

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(9), P. 1237 - 1237

Published: April 25, 2023

Although previously restricted to a limited number of medical conditions, there is growing appreciation that 'autoimmune' (or immune-mediated) processes are important aspects wide array diverse including cancers, neurodegenerative diseases and psychiatric disorders. All these classes conditions associated with alterations in mitochondrial function across an cell types. Accumulating data indicate the presence melatonergic pathway possibly all body cells, consequences for pathways crucial driving CD8+ T B-cell 'autoimmune'-linked processes. Melatonin suppression coupled upregulation oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising levels major histocompatibility complex (MHC)-1, which underpins chemoattraction cells activation antibody-producing B-cells. Many factors closely autoimmunity, gut microbiome/permeability, circadian rhythms, aging, aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) its receptor tyrosine B (TrkB) interact pathway. A future research directions novel treatment implications indicated this collection poorly conceptualized treated presentations. It proposed etiology many 'autoimmune'/'immune-mediated' disorders should be as significantly determined by dysregulation, being aspect pathoetiologies.

Language: Английский

Citations

Signaling to survive: linear ubiquitination in health and disease DOI

Gulustan Celik,

Nadine Weinelt, Sjoerd J. L. van Wijk

et al.

BIOspektrum, Journal Year: 2025, Volume and Issue: 31(1), P. 32 - 35

Published: Feb. 1, 2025

Language: Английский

Citations