Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(11), С. 926 - 946

Опубликована: Авг. 6, 2024

Язык: Английский

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ATG9A facilitates the closure of mammalian autophagosomes

The Journal of Cell Biology, Год журнала: 2025, Номер 224(2)

Опубликована: Янв. 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.

Язык: Английский

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Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 7, 2025

ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number biological outputs includes control tuberculosis in animal models. Here, we show that associates retromer’s components VPS26, VPS29, and VPS35 modulates retromer function. Knockout blocked trafficking key glucose transporter sorted by retromer, GLUT1, to plasma membrane. Knockouts other genes essential for component, affected GLUT1 sorting, indicating atg8ylation process affects function endosomal sorting. The contribution sorting was independent canonical autophagy. These findings expand scope specific processes cell dependent on its known interactors.

Язык: Английский

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Canonical and noncanonical autophagy: involvement in Parkinson’s disease

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Янв. 30, 2025

Autophagy is the major degradation process in cells and involved a variety of physiological pathological functions. While macroautophagy, which employs series molecular cascades to form ATG8-coated double membrane autophagosomes for degradation, remains well-known type canonical autophagy, microautophagy chaperon-mediated autophagy have also been characterized. On other hand, recent studies focused on functions proteins beyond intracellular including noncanonical known as conjugation ATG8 single membranes (CASM), autophagy-related extracellular secretion. In particular, CASM unique that it does not require upstream mechanisms, while system manner different from autophagy. There many reports involvement these mechanisms neurodegenerative diseases, with Parkinson’s disease (PD) receiving particular attention because important roles several causative risk genes, LRRK2. this review, we will summarize discuss contributions cellular functions, special focus pathogenesis PD.

Язык: Английский

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Cellular homeostatic responses to lysosomal damage

Trends in Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Bridge-like lipid transfer protein 3A (BLTP3A) is associated with membranes of the late endocytic pathway and is an effector of CASM

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 28, 2024

Recent studies have identified a family of rod-shaped proteins which includes VPS13 and ATG2 are thought to mediate unidirectional lipid transport at intracellular membrane contacts by bridge-like mechanism. Here, we show that one such protein, BLTP3A/UHRF1BP1, associates with VAMP7-positive vesicles via its C-terminal region anchors them lysosomes the binding chorein domain containing N-terminal Rab7. Upon damage lysosomal membranes resulting mATG8 recruitment their surface CASM, BLTP3A first dissociates from but then reassociates an interaction LIR motif mATG8. Such is mutually exclusive leaves domain, i.e. proposed entry site lipids into this proteins, available for another membrane, possibly ER. Our findings reveal effector potentially as part mechanism help repair or minimize lysosome delivering lipids.

Язык: Английский

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Molecular Mechanisms Underlying Initiation and Activation of Autophagy

Biomolecules, Год журнала: 2024, Номер 14(12), С. 1517 - 1517

Опубликована: Ноя. 27, 2024

Autophagy is an important catabolic process to maintain cellular homeostasis and antagonize stresses. The initiation activation are two of the most aspects autophagic process. This review focuses on mechanisms underlying autophagy signaling pathways regulating found in recent years. These findings include by liquid–liquid phase separation (LLPS), endoplasmic reticulum (ER) Golgi apparatus, mediated ULK1 complex, mTOR AMPK PI3KC3 complex. Through review, we attempt present current research progress regulation forward our understanding regulatory activation.

Язык: Английский

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Keeping your endosymbiont under control: the enigmatic plastid membrane ATG8ylation in Apicomplexa parasites

Autophagy, Год журнала: 2025, Номер unknown, С. 1 - 5

Опубликована: Март 24, 2025

ATG8ylation of membranes has been increasingly reported over the last few years, in various configurations and across different eukaryotic models. While unconventional conjugation ATG8 to outermost membrane plastid apicomplexan parasites was first observed a decade ago, it is often overlooked literature reviews focusing on non-autophagosomal membranes. Here, I provide brief overview current knowledge these discuss possible parallel between evolutionary origin this other processes, such as LC3-associated phagocytosis.

Язык: Английский

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Mycobacterium tuberculosis phagosome Ca ²⁺ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages

Science Advances, Год журнала: 2025, Номер 11(13)

Опубликована: Март 26, 2025

The role of canonical autophagy in controlling Mycobacterium tuberculosis (Mtb), referred to as xenophagy, is understood involve targeting Mtb autophagosomes, which subsequently fuse with lysosomes for degradation. Here, we found that Ca 2+ leakage after phagosome damage human macrophages the signal triggers autophagy-related protein 8/microtubule-associated proteins 1A/1B light chain 3 (ATG8/LC3) lipidation. Unexpectedly, ATG8/LC3 lipidation did not target lysosomes, excluding xenophagy. Upon damage, leakage–dependent occurred on multiple membranes instead single or double noncanonical pathways. Mechanistically, from triggered recruitment V-ATPase–ATG16L1 complex independently FIP200, ATG13, and proton gradient disruption. Furthermore, limited restricted replication. Together, uncovered key mitigate damage.

Язык: Английский

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Lysosomal Repair in Health and Disease

Journal of Cellular Physiology, Год журнала: 2025, Номер 240(5)

Опубликована: Май 1, 2025

ABSTRACT Lysosomes are essential organelles degrading a wide range of substrates, maintaining cellular homeostasis, and regulating cell growth through nutrient metabolic signaling. A key vulnerability lysosomes is their membrane permeabilization (LMP), process tightly linked to diseases including aging, neurodegeneration, lysosomal storage disorders, cardiovascular disease. Research progress in the past few years has greatly improved our understanding repair mechanisms. Upon LMP, cells activate multiple remodeling processes restore integrity, such as invagination, tubulation, lipid patching, stabilization. These pathways critical preserving stress tolerance preventing deleterious inflammation death triggered by damage. This review focuses on expanding mechanistic insights repair, highlighting its crucial role health implications for disease pathogenesis therapeutic strategies.

Язык: Английский

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