Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168691 - 168691
Published: June 27, 2024
Language: Английский
The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(7)
Published: June 5, 2023
Two papers in this issue resolve a long-standing obstacle to “standard model” for autophagosome biogenesis mammals. The first, Olivas et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202208088), uses biochemistry confirm that the lipid scramblase ATG9A is bona fide component, while second, Broadbent https://doi.org/10.1083/jcb.202210078), particle tracking show dynamics of autophagy proteins are consistent with concept.
Language: Английский
Citations
16
PLoS Biology, Journal Year: 2023, Volume and Issue: 21(4), P. e3002030 - e3002030
Published: April 13, 2023
Autophagy is essential for cellular homeostasis and function. In neurons, autophagosome biogenesis temporally spatially regulated to occur near presynaptic sites, in part via the trafficking of autophagy transmembrane protein ATG-9. The molecules that regulate by sorting ATG-9 at synapses remain largely unknown. Here, we conduct forward genetic screens single C. elegans neurons identify a role long isoform active zone Clarinet (CLA-1L) regulating synapses, autophagy. We determine disrupting CLA-1L results abnormal accumulation containing vesicles enriched with clathrin. phenotype cla-1(L) mutants not observed other synaptic vesicle proteins, suggesting distinct mechanisms ATG-9-containing vesicles. Through analyses, uncover adaptor complexes genetically interact CLA-1 sorting. also extends from periactive interacts proteins Our findings reveal novel roles
Language: Английский
Citations
14
Autophagy, Journal Year: 2023, Volume and Issue: 20(4), P. 883 - 901
Published: Oct. 26, 2023
In neurons, autophagosome biogenesis occurs mainly in distal axons, followed by maturation during retrograde transport. Autophagosomal growth depends on the supply of membrane lipids which requires small vesicles containing ATG9, a lipid scramblase essential for macroautophagy/autophagy. Here, we show that ATG9-containing are enriched synapses and resemble synaptic size density. The proteome immuno-isolated from nerve terminals showed conspicuously low levels trafficking proteins except AP2-complex some enzymes involved endosomal phosphatidylinositol metabolism. Super resolution microscopy isolated revealed represent distinct vesicle population with limited overlap not only but also other membranes secretory pathway, uncovering surprising heterogeneity their composition. Our results compatible view function as shuttles scavenge various intracellular to support biogenesis.
Language: Английский
Citations
13
The Plant Cell, Journal Year: 2024, Volume and Issue: 36(9), P. 3009 - 3024
Published: March 27, 2024
Autophagy is one of the major highly inducible degradation processes in response to plant developmental and environmental signals. In different stimuli, cellular materials, including proteins organelles, can be sequestered into a double membrane autophagosome structure either selectively or nonselectively. The formation an as well its delivery vacuole involves complex dynamic processes. identification characterization conserved autophagy-related (ATG) their related regulators have greatly advanced our understanding molecular mechanism underlying biogenesis function cells. Autophagosome tightly regulated by coordination multiple ATG non-ATG selective cargo recruitment. This review updates current knowledge biogenesis, with special emphasis on core machinery that drives autophagosome-organelle interactions under abiotic stress conditions.
Language: Английский
Citations
5
The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(8)
Published: May 22, 2024
Autophagy is an important metabolic pathway that can non-selectively recycle cellular material or lead to targeted degradation of protein aggregates damaged organelles. Autophagosome formation starts with autophagy factors accumulating on lipid vesicles containing ATG9. These phagophores attach donor membranes, expand via ATG2-mediated transfer, capture cargo, and mature into autophagosomes, ultimately fusing lysosomes for their degradation. be activated by nutrient stress, example, a reduction in the levels amino acids. In contrast, how regulated low ATP AMP-activated kinase (AMPK), therapeutic target, less clear. Using live-cell imaging automated image analysis pipeline, we systematically dissect starvation regulates autophagosome biogenesis. We demonstrate glucose downregulates maturation AMPK-mediated inhibition phagophore tethering membrane. Our results clarify AMPKs regulatory role highlight its potential as target reduce autophagy.
Language: Английский
Citations
5
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
Citations
4
Cell Reports, Journal Year: 2024, Volume and Issue: 43(9), P. 114689 - 114689
Published: Aug. 27, 2024
Autophagy initiation is regulated by the ULK1 kinase complex. To gain insights into functions of holo-complex, we generated a deep interactome combining affinity purification- and proximity labeling-mass spectrometry all four complex members: ULK1, ATG13, ATG101, RB1CC1/FIP200. Under starvation conditions, interacts with several protein lipid kinases phosphatases, implying formation signalosome. Interestingly, selective autophagy receptors also interact indicating activation pathways nutrient starvation. One effector HSC/HSP70 co-chaperone BAG2, which regulates subcellular localization VPS34 member AMBRA1. Depending on nutritional status, BAG2 has opposing roles. In growth unphosphorylated form sequesters AMBRA1, attenuating induction. phosphorylates Ser31, supports recruitment AMBRA1 to ER membrane, positively affecting autophagy.
Language: Английский
Citations
4
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
Citations
0
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
Citations
0
The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown
Published: March 24, 2025
Abstract Lipid transfer proteins mediate the non-vesicular transport of lipids at membrane contact sites to regulate lipid composition organelle membranes. Despite significant recent advances in our understanding structural basis for transfer, its functional regulation remains unclear. In this study, we report that S-palmitoylation modulates cellular function ATG2, a rod-like protein responsible transporting phospholipids from endoplasmic reticulum (ER) phagophores during autophagosome formation. During starvation-induced autophagy, ATG2A undergoes depalmitoylation as balance between ZDHHC11-mediated palmitoylation and APT1-mediated depalmitoylation. Inhibition leads impaired formation disrupted autophagic flux. Further, cell vitro analyses demonstrate C-terminus anchors ER. Depalmitoylation detaches ER membrane, enabling it interact with promoting their growth. These findings elucidate S-palmitoylation-dependent regulatory mechanism which may represent broad strategy mediated by bridge-like transporters within cells.
Language: Английский
Citations
0