The Epstein-Barr virus deubiquitinase BPLF1 regulates stress-induced ribosome UFMylation and reticulophagy

Autophagy, Год журнала: 2025, Номер unknown, С. 1 - 23

Опубликована: Янв. 22, 2025

The synthesis of membrane and secreted proteins is safeguarded by an endoplasmic reticulum-associated ribosome quality control (ER-RQC) that promotes the disposal defective translation products proteasome or via a lysosome-dependent pathway involving degradation portions ER macroautophagy (reticulophagy). UFMylation RPL26 on ER-stalled ribosomes essential for activating ER-RQC reticulophagy. Here, we report viral deubiquitinase (vDUB) encoded in N-terminal domain Epstein-Barr virus (EBV) large tegument protein BPLF1 hinders stall at ER, stabilization substrates, inhibits vDUB did not act as de-UFMylase interfere with CYB5R3 UFL1 ligase. Instead, it copurified sucrose gradients abrogated ZNF598- LTN1-independent ubiquitination event required UFMylation. Physiological levels impaired productively EBV-infected cells, pointing to important role enzyme regulating allows efficient production infectious virus.

Язык: Английский

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Missense variants in GABAA receptor beta2 subunit disrupt receptor biogenesis and cause loss of function

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Gamma-aminobutyric acid type A receptors (GABA Rs) are the major inhibitory neurotransmitter-gated channel in mammalian central nervous system. GABA Rs function as heteropentamers, typically composed of two α1, β2, and one γ2 subunits. Protein homeostasis between R folding, trafficking, assembly, degradation is critical to ensure normal physiological functions. Variants genes encoded for lead numerous neurological disorders, such genetic epilepsy with or without neurodevelopmental delay. While these variants associated severe clinical presentations epilepsy, molecular mechanisms driving disease remain be elucidated. In this study, we focused on four missense epilepsy-associated (EAVs) GABRB2 gene: Q209F210delinsH (c. 627_629del), R240T 719G>C), I246T 737T>C), I299S 896T>G). HEK293T cells exogenously expressing β2 exhibited significantly reduced GABA-induced peak chloride current, indicating their loss function. However, EAVs differed degree proteostasis deficiencies, including increased ER retention, compromised decreased protein stability, trafficking surface expression, leading most degradation. Collectively, results indicate that epilepsy-linked have debilitating effects early biogenesis subunit, causing misfolding, aggregation, rapid before it can assembled other subunits transported plasma membrane. Overall, our work offers crucial mechanistic insight into how specific impact maintenance Rs, which could facilitate development effective therapeutics by targeting trafficking-deficient variants.

Язык: Английский

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DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis

Cell Death and Disease, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 17, 2024

Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER-associated degradation (ER-phagy) in pathogenesis of AKI. We employed four distinct murine models AKI-induced contrast media, ischemia-reperfusion injury, cisplatin, folic acid-to elucidate relationship ER-phagy, ER apoptosis. Our findings reveal marked decrease ER-phagy coinciding with an accumulation damaged ER, increased apoptosis across all AKI models. Importantly, overexpression DDRGK1 HK-2 cells enhanced levels, ameliorating contrast-induced stress These unveil novel protective mechanism AKI, wherein DDRGK1-UFL1-mediated mitigates renal tubular epithelial cells. results thereby contribute to understanding molecular underpinnings offer potential therapeutic targets for its treatment.

Язык: Английский

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Endoplasmic Reticulum Stress Underlies Nanosilver-Induced Neurotoxicity in Immature Rat Brain

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(21), С. 13013 - 13013

Опубликована: Окт. 27, 2022

The growing production of silver nanoparticles (AgNPs), and their widespread use in medical consumer products, poses a potential threat to the environment raises questions about biosafety. Immature organisms are particularly susceptible various insults during development. biological characteristics immature different from those adults, dictate consequences exposure toxic substances, including AgNPs. Nanoparticles highly reactive can easily cross blood-brain barrier (BBB) accumulate brain tissues. It is therefore important investigate molecular mechanisms AgNP-induced neurotoxicity developing brain. 2-week-old rats were exposed low dose AgNPs (0.2 mg/kg b.w.) over long period. Subsequently, tissues animals subjected ultrastructural analyses determine endoplasmic reticulum (ER) stress. Ultrastructural markers ER stress, such as pathological alterations elongated forms mitochondria accompanied by autophagy structures, confirmed be present AgNP-exposed rat Evidence for induction stress neurons was also provided markers. Upregulation genes related ER-stress-induced unfolded protein response (UPR) pathway, GRP78, PERK, CHOP ATF-6, observed at transcriptional translational levels. results show that prolonged developmental period leads Simultaneously, promote protective partially compensate regulating biodynamic processes autophagy.

Язык: Английский

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ER‐phagy in neurodegeneration

Journal of Neuroscience Research, Год журнала: 2023, Номер 101(10), С. 1611 - 1623

Опубликована: Июнь 19, 2023

Abstract There are many cellular mechanisms implicated in the initiation and progression of neurodegenerative disorders. However, age accumulation unwanted products a common theme underlying diseases including Alzheimer's disease, Parkinson's Niemann–Pick type C. Autophagy has been studied extensively these various genetic risk factors have disruption autophagy homoeostasis as major pathogenic mechanism. is essential maintenance neuronal homeostasis, their postmitotic nature makes them particularly susceptible to damage caused by defective or misfolded proteins, disease‐prone aggregates, damaged organelles. Recently, endoplasmic reticulum (ER‐phagy) identified novel mechanism for regulating ER morphology response stress. As generally precipitated stressors such protein environmental toxin exposure role ER‐phagy begun be investigated. In this review we discuss current research its involvement diseases.

Язык: Английский

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