Combinatorial selective ER-phagy remodels the ER during neurogenesis

Nature Cell Biology, Год журнала: 2024, Номер 26(3), С. 378 - 392

Опубликована: Март 1, 2024

The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis calcium ion flux inter-organelle communication. A case in point concerns the process of neurogenesis, where refined tubular ER network is assembled via shaping proteins into newly formed neuronal projections create highly polarized dendrites axons. Previous studies have suggested role for autophagy remodelling, as autophagy-deficient neurons vivo display axonal accumulation within synaptic boutons, membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory autonomic neuropathy. However, our understanding mechanisms underlying selective removal individual receptors limited. Here we combine tractable induced neuron (iNeuron) system monitoring remodelling during vitro differentiation proteomic computational tools quantitative autophagy. Through analysis single combinatorial mutants, delineate extent which each contributes both magnitude selectivity clearance. We define specific subsets membrane or lumenal preferred clients distinct receptors. Using spatial sensors reporters, demonstrate receptor-specific autophagic capture axons, directly visualize membranes autophagosomes by cryo-electron tomography. This molecular inventory versatile genetic toolkit provide framework contributions reshaping cell state transitions.

Язык: Английский

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The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria

Cellular and Molecular Life Sciences, Год журнала: 2025, Номер 82(1)

Опубликована: Янв. 12, 2025

Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through continuous accumulation misfolded proteins and damaged organelles. This review delineates roles two complementary synergistic degradation systems, ubiquitin–proteasome system (UPS) autophagy-lysosome system, in organelles for intracellular recycling. We emphasize interconnected decision-making processes systems maintaining homeostasis, such as biophysical state substrates, receptor oligomerization potentials (e.g., p62), compartmentalization capacities membrane structures). Mitochondria, hubs respiration metabolism, are implicated tumorigenesis. In subsequent sections, we thoroughly examine mechanisms mitochondrial quality control (MQC) preserving human cells. Notably, explored relationships between dynamics (fusion fission) various MQC processes—including UPS, proteases, mitophagy—in context repair pathways. Finally, assessed potential targeting (including molecular chaperones, dynamics, mitophagy biogenesis) therapeutic strategies. Understanding underlying may offer novel insights future therapies. highlights UPS degrading proteins, emphasizing substrate states, oligomerization, homeostasis. Innovatively links coordination to examining interplay these pathways varying degrees damage.

Язык: Английский

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Golgi organization is regulated by proteasomal degradation

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Янв. 21, 2020

Abstract The Golgi is a dynamic organelle whose correct assembly crucial for cellular homeostasis. Perturbations in structure are associated with numerous disorders from neurodegeneration to cancer. However, whether and how dispersal of the apparatus actively regulated under stress, consequences dispersal, remain unknown. Here we demonstrate that 26S proteasomes cytosolic surface membranes facilitate Apparatus-Related Degradation (GARD) degradation GM130 response stress. dependent on p97/VCP proteasomes, required dispersal. Finally, show perturbation homeostasis induces cell death multiple myeloma vitro vivo, offering therapeutic strategy this malignancy. Taken together, work reveals mechanism Golgi-localized proteasomal degradation, providing functional link between proteostasis control architecture, which may be critical various secretion-related pathologies.

Язык: Английский

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The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Biomedicines, Год журнала: 2021, Номер 9(2), С. 156 - 156

Опубликована: Фев. 5, 2021

Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches the Unfolded Protein Response (UPR) signaling pathway, which activated upon endoplasmic reticulum (ER) stress conditions. It known to be capable inducing both pro-survival and pro-apoptotic cellular responses, are strictly related numerous human pathologies. Among others, IRE1 activity has been confirmed increased in cancer, neurodegeneration, inflammatory metabolic disorders, associated with an accumulation misfolded proteins within ER lumen resulting Emerging evidence suggests that genetic or pharmacological modulation may have significant impact on cell viability, thus promising step forward towards development novel therapeutic strategies. In this review, we extensively describe structural analysis molecule, molecular dynamics activation, interconnection between it other UPR regard its potential use target. Detailed knowledge characteristics protein activation allow design specific RNase modulators act drug candidates.

Язык: Английский

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ER-phagy and human diseases

Cell Death and Differentiation, Год журнала: 2019, Номер 27(3), С. 833 - 842

Опубликована: Окт. 28, 2019

Язык: Английский

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Endosome and Golgi‐associated degradation ( EGAD ) of membrane proteins regulates sphingolipid metabolism

The EMBO Journal, Год журнала: 2019, Номер 38(15)

Опубликована: Май 27, 2019

Cellular homeostasis requires the ubiquitin-dependent degradation of membrane proteins. This was assumed to be mediated exclusively either by endoplasmic reticulum-associated (ERAD) or endosomal sorting complexes required for transport (ESCRT)-dependent lysosomal degradation. We identified in Saccharomyces cerevisiae an additional pathway that selectively extracts proteins at Golgi and endosomes cytosolic proteasomes. One endogenous substrate this endosome Golgi-associated (EGAD) is ER-resident protein Orm2, a negative regulator sphingolipid biosynthesis. Orm2 initiated phosphorylation, which triggers its ER export. Once on endosomes, poly-ubiquitinated membrane-embedded "Defective SREBP cleavage" (Dsc) ubiquitin ligase complex. Cdc48/VCP then ubiquitinated from membranes, tightly coupled proteasomal Orm2. Thereby, EGAD prevents accumulation post-ER compartments promotes controlled de-repression Thus, selective contributes proteostasis lipid eukaryotic cells.

Язык: Английский

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ER-phagy responses in yeast, plants, and mammalian cells and their crosstalk with UPR and ERAD

Developmental Cell, Год журнала: 2021, Номер 56(7), С. 949 - 966

Опубликована: Март 24, 2021

Язык: Английский

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Review: ER stress-induced cell death in osteoarthritic cartilage

Cellular Signalling, Год журнала: 2020, Номер 78, С. 109880 - 109880

Опубликована: Дек. 8, 2020

In cartilage, chondrocytes are responsible for the biogenesis and maintenance of extracellular matrix (ECM) composed proteins, glycoproteins proteoglycans. Various cellular stresses, such as hypoxia, nutrient deprivation, oxidative stress or accumulation advanced glycation end products (AGEs) during aging, but also translational errors mutations in cartilage components chaperone proteins affect synthesis secretion ECM causing protein aggregates to accumulate endoplasmic reticulum (ER). This condition, referred ER stress, interferes with cell homeostasis initiates unfolded response (UPR), a rescue mechanism regain viability function. Chronic irreversible however, triggers UPR-initiated death. Due unresolved chondrocytes, diseases skeletal system, chondrodysplasias, arise. has been identified contributing factor pathogenesis degeneration processes osteoarthritis (OA). review provides current knowledge about describes possible causes impairment involved focuses on stress-induced death articular OA. Targeting itself intervention UPR signaling reduce may be promising future therapy.

Язык: Английский

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Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER‐phagy, and Collagen quality control

EMBO Reports, Год журнала: 2021, Номер 22(9)

Опубликована: Авг. 2, 2021

Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon induction ER stress signal, they can induce significant fragmentation subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, FAM134C are essential maintaining morphology a LC3-interacting region (LIR)-dependent manner. Overexpression any FAM134 paralogue has capacity to significantly augment general flux upon starvation or ER-stress. Global proteomic analysis overexpressing knockout cell lines reveals several protein clusters that distinctly regulated by each paralogues well cluster commonly ER-resident proteins. Utilizing pro-Collagen I, shared substrate, we observe FAM134A acts LIR-independent manner compensates loss FAM134B FAM134C, respectively. instead unable compensate its paralogues. Taken together, our data show contribute common unique pathways.

Язык: Английский

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Membrane Protein Quality Control Mechanisms in the Endo-Lysosome System

Trends in Cell Biology, Год журнала: 2021, Номер 31(4), С. 269 - 283

Опубликована: Янв. 4, 2021

Язык: Английский

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