ATG9A facilitates the closure of mammalian autophagosomes

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(2)

Published: Jan. 2, 2025

Canonical autophagy captures within specialized double-membrane organelles, termed autophagosomes, an array of cytoplasmic components destined for lysosomal degradation. An autophagosome is completed when the growing phagophore undergoes ESCRT-dependent membrane closure, a prerequisite its subsequent fusion with endolysosomal organelles and degradation sequestered cargo. ATG9A, key integral protein pathway, best known role in formation expansion phagophores. Here, we report hitherto unappreciated function mammalian ATG9A directing closure. partners IQGAP1 ESCRT-III component CHMP2A to facilitate this final stage formation. Thus, central hub governing all major aspects biogenesis, from unique ATG factor progressive functionalities affecting physiological outputs autophagy.

Language: Английский

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Trafficking of K63-polyubiquitin modified membrane proteins in a macroautophagy-independent pathway is linked to ATG9A

Molecular Biology of the Cell, Journal Year: 2025, Volume and Issue: 36(4)

Published: Feb. 19, 2025

Cytoplasmic K63-linked polyubiquitin signals have well-established roles in endocytosis and selective autophagy. However, how these help to direct different cargos intracellular trafficking routes is unclear. Here we report that, when the K63-polyubiquitin signal blocked by expression of a high-affinity sensor (named Vx3), many proteins originating from plasma membrane are found trapped clusters small vesicles that colocalize with ATG9A, transmembrane protein plays an essential role Importantly, whereas ATG9A required for cluster formation, other core autophagy machinery as well cargo receptors not required. Although sequestered vesicular ATG9-dependent manner, additional needed induce LC3 conjugation. Upon removal Vx3 block, K63-polyubiquitylated rapidly delivered lysosomes. These observations suggest unexpected K63-polyubiquitin–modified proteins.

Language: Английский

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Neuronal autophagy in the control of synapse function

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Neurons are long-lived postmitotic cells that capitalize on autophagy to remove toxic or defective proteins and organelles maintain neurotransmission the integrity of their functional proteome. Mutations in genes cause congenital diseases, sharing prominent brain dysfunctions including epilepsy, intellectual disability, neurodegeneration. Ablation core neurons glia disrupts normal behavior, leading motor deficits, memory impairment, altered sociability, which associated with defects synapse maturation, plasticity, neurotransmitter release. In spite importance for physiology, substrates neuronal mechanisms by affect synaptic function health disease remain controversial. Here, we summarize current state knowledge autophagy, address existing controversies inconsistencies field, provide a roadmap future research role control function.

Language: Английский

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The life and times of brain autophagic vesicles

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169105 - 169105

Published: March 1, 2025

Language: Английский

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Kremen1 dependence receptor induces SEC24C- and ATG9A-dependent autophagic cell death

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

ABSTRACT Dependence receptors (DRs) induce cell death by apoptosis in the absence of their ligand. Among them, Kremen1 was first described to cancer its ligand, DKK1. Nevertheless, exact mechanism Kremen1-triggered remains unexplored. In this study, we demonstrate that induces with autophagic features, contrasting apoptotic process typically associated dependence receptors. Specifically, chemical inhibition autophagy spautin or wortmannin genetic ATG9A ATG18B effectively blocks process. Furthermore, through a proximity protein interactome analysis Kremen1, identified Sec24C, component COP-II complex, as important effector Kremen1-induced and death. Our findings reveal an interaction between Sec24C ATG8 regulated potentially underlying increased number autophagosomes cells, leading This correlation induction aberrant deserves particular attention, especially Kremen1/DKK1 pair is frequently altered cancers, higher DKK1 expression poor survival outcomes. Thus, targeting pathway may offer potential strategy for treating cancers resistant current therapies.

Language: Английский

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Mitophagy at the oocyte-to-zygote transition promotes species immortality

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Abstract The quality of inherited mitochondria determines embryonic viability 1 , metabolic health during adulthood and future generation endurance. oocyte is the source all zygotic 2 mitochondrial under strict developmental regulation early oogenesis 3–5 . Yet, fully developed oocytes exhibit presence deleterious DNA (mtDNA) 6,7 dysfunction from high levels endogenous reactive oxygen species 8 exogenous toxicants 9 How prevent transmission damaged to zygotes unknown. Here we discover that onset oocyte-to-zygote transition (OZT) developmentally triggers a robust rapid mitophagy event term at OZT (MOZT). We show MOZT requires fragmentation, activation macroautophagy system receptor FUNDC1, but not prevalent factors PINK1 BNIP3. Oocytes upregulate expression FUNDC1 in response diverse insults, including mtDNA mutations damage, uncoupling stress, dysfunction, thereby promoting selection against mitochondria. Loss leads increased inheritance impaired bioenergetic progeny, resulting diminished extinction descendent populations. Our findings reveal FUNDC1-mediated as mechanism preserves mother-to-offspring promotes continuity. These results may explain how mature many harboring mutant give rise healthy embryos with reduced mtDNA.

Language: Английский

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Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Feb. 28, 2025

Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in WDR45 . Currently, there no cure or altering treatment for this disease. This is, part, due lack of insight into early phenotypes BPAN progression ’s role establishing maintaining neurological function. Here we generated characterized mouse model bearing c52C > T patient variant Wdr45. We show mutation ablates protein expression alters autophagy the brain. Behavioral analysis these mice revealed characteristic signs including cognitive impairment, hyperactivity, motor decline. behaviors coincide with widespread glial activation development axonal spheroids multiple neuron subclasses throughout Several lines evidence suggest arise from axon terminals. Transcriptomic uncovered disrupted pathways cortex genes associated synapses, neurites, endosomes, endoplasmic reticulum, ferroptosis. supported by accumulation iron regulating transferrin receptor 1 (TFRC) reticulum resident calreticulin (CALR) as animals age. CALR forms spheroid structures similar seen animals. Taken together, our data that necessary healthy brain function maintenance opens door therapeutics targeting further exploration neuronal

Language: Английский

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Faa1 membrane binding drives positive feedback in autophagosome biogenesis via fatty acid activation

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(7)

Published: April 4, 2024

Autophagy serves as a stress response pathway by mediating the degradation of cellular material within lysosomes. In autophagy, this is encapsulated in double-membrane vesicles termed autophagosomes, which form from precursors referred to phagophores. Phagophores grow lipid influx endoplasmic reticulum into Atg9-positive compartments and local synthesis provides lipids for their expansion. How phagophore nucleation expansion are coordinated with unclear. Here, we show that Faa1, an enzyme activating fatty acids, recruited Atg9 directly binding negatively charged membranes preference phosphoinositides such PI3P PI4P. We define membrane-binding surface Faa1 its direct interaction membrane required recruitment Furthermore, physiological localization key efficient catalysis promotes Our results suggest positive feedback loop coupling synthesis.

Language: Английский

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Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology

Autophagy, Journal Year: 2024, Volume and Issue: 20(11), P. 2373 - 2387

Published: Aug. 4, 2024

Atg9, the only transmembrane protein among many autophagy-related proteins, was first identified in year 2000 yeast. Two homologs of ATG9A and ATG9B, have been found mammals. While ATG9B shows a tissue-specific expression pattern, such as placenta pituitary gland, is ubiquitously expressed. Additionally, deficiency leads to severe defects not at molecular cellular levels but also organismal level, suggesting key fundamental roles for ATG9A. The subcellular localization on small vesicles its functional relevance autophagy suggested potential role lipid supply during autophagosome biogenesis. Nevertheless, precise autophagic process has remained long-standing mystery, especially neurons. Recent findings, however, including structural, proteomic, biochemical analyses, provided new insights into function expansion phagophore membrane. In this review, we aim understand various aspects ATG9 (in invertebrates plants)/ATG9A mammals), localization, trafficking, other functions, nonneuronal cells neurons by comparing recent discoveries related ATG9/ATG9A proposing directions future research.

Language: Английский

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TgATG9 is required for autophagosome biogenesis and maintenance of chronic infection in Toxoplasma gondii

Autophagy Reports, Journal Year: 2024, Volume and Issue: 3(1)

Published: Oct. 23, 2024

is a ubiquitous protozoan parasite that can reside long-term within hosts as intracellular tissue cysts comprised of chronic stage bradyzoites. To perturb infection requires better understanding the cellular processes mediate persistence. Macroautophagy/autophagy catabolic and homeostatic pathway required for

Language: Английский

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