Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(8), P. 1501 - 1513

Published: March 31, 2022

Selective autophagy specifically eliminates damaged or superfluous organelles, maintaining cellular health. In this process, a double membrane structure termed an autophagosome captures target organelles proteins and delivers cargo to the lysosome for degradation. The attachment of small protein ubiquitin has emerged as common mechanism initiating organelle capture by machinery. suite ubiquitin-binding receptors function initiate assembly in situ on cargo, thereby providing selectivity capture. Here, we review recent efforts understand biochemical mechanisms principles which are marked with how use conserved structural modules recruit initiation machinery, particular focus mitochondria intracellular bacteria cargo. These emerging provide answers long-standing questions field concerning degradation is achieved.

Language: Английский

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Orchestration of selective autophagy by cargo receptors

Current Biology, Journal Year: 2022, Volume and Issue: 32(24), P. R1357 - R1371

Published: Dec. 1, 2022

Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for degradation such cargo This is achieved by sequestration within double-membrane vesicles termed autophagosomes, which form de novo around subsequently deliver their content to lysosomes degradation. The importance selective exemplified various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia. It has become evident that receptors are acting as Swiss army knives recognizing cargo, orchestrating recruitment machinery autophagosome biogenesis, closely aligning membrane cargo. Furthermore, sequester ubiquitinated proteins into larger condensates upstream induction. Here, we review recent insights mechanisms action focusing on roles sequestosome-like misfolded, mitochondria. We also highlight at steps function result accumulation harmful material how knowledge may guide design future therapies.

Language: Английский

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Autophagy in health and disease: From molecular mechanisms to therapeutic target

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 10, 2022

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over past two decades, autophagy has been extensively studied, from molecular mechanisms, biological functions, implications various human diseases, development of autophagy-related therapeutics. This review will focus on latest research, covering mechanisms control biogenesis autophagosome-lysosome fusion, upstream regulatory pathways including AMPK MTORC1 pathways. We also provide a systematic discussion implication cancer, neurodegenerative disorders (Alzheimer disease, Parkinson Huntington's Amyotrophic lateral sclerosis), metabolic diseases (obesity diabetes), viral infection especially SARS-Cov-2 COVID-19, cardiovascular (cardiac ischemia/reperfusion cardiomyopathy), aging. Finally, we summarize pharmacological agents that have therapeutic potential clinical applications via targeting pathway. It believed decades hard work research eventually bring real tangible benefits improvement health diseases.

Language: Английский

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Autophagy restricts Mycobacterium tuberculosis during acute infection in mice

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(5), P. 819 - 832

Published: April 10, 2023

Language: Английский

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Quantitative analysis of autophagy reveals the role of ATG9 and ATG2 in autophagosome formation

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(7)

Published: April 28, 2023

Autophagy is a catabolic pathway required for the recycling of cytoplasmic materials. To define mechanisms underlying autophagy it critical to quantitatively characterize dynamic behavior factors in living cells. Using panel cell lines expressing HaloTagged from their endogenous loci, we analyzed abundance, single-molecule dynamics, and autophagosome association kinetics proteins involved biogenesis. We demonstrate that formation inefficient ATG2-mediated tethering donor membranes key commitment step formation. Furthermore, our observations support model phagophores are initiated by accumulation on mobile ATG9 vesicles, ULK1 complex PI3-kinase form positive feedback loop Finally, duration biogenesis ∼110 s. In total, work provides quantitative insight into establishes an experimental framework analyze human

Language: Английский

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Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation

Science Advances, Journal Year: 2023, Volume and Issue: 9(7)

Published: Feb. 15, 2023

The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in PINK1- and Parkin-dependent mitophagy pathway implicated Parkinson's disease. structural interaction between sole transmembrane protein, autophagy-related protein 9A (ATG9A), components Unc-51-like activating kinase (ULK1) complex is one major missing links needed to complete a map initiation. We determined 2.4-Å x-ray crystallographic structure ternary ATG9A carboxyl-terminal tail bound ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which part ULK1 complex. term interacting portion extreme "HORMA dimer-interacting region" (HDIR). This shows that HDIR binds HORMA domain ATG101 by β sheet complementation such resides deep cleft at interface. Disruption this cells impairs damage-induced PINK1/Parkin mediated cargo receptor NDP52.

Language: Английский

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Combinatorial selective ER-phagy remodels the ER during neurogenesis

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 378 - 392

Published: March 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.

Language: Английский

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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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Molecular mechanisms of endomembrane trafficking in plants

The Plant Cell, Journal Year: 2021, Volume and Issue: 34(1), P. 146 - 173

Published: Sept. 17, 2021

Abstract Endomembrane trafficking is essential for all eukaryotic cells. The best-characterized membrane organelles include the endoplasmic reticulum (ER), Golgi apparatus, early and recycling endosomes, multivesicular body, or late endosome, lysosome/vacuole, plasma membrane. Although historically plants have given rise to cell biology, our understanding of has mainly been shaped by much more studied mammalian yeast models. Whereas major protein families that regulate endomembrane are largely conserved across eukaryotes, exciting variations emerging from advances in plant biology research. In this review, we summarize current state knowledge on trafficking, with a focus four distinct pathways: ER-to-Golgi transport, endocytosis, trans-Golgi network-to-vacuole autophagy. We acknowledge conservation commonalities machinery species, emphasis diversity plant-specific features. Understanding function currently nonexistent well-known model organisms will provide great opportunities acquire new insights into fundamental cellular process trafficking.

Language: Английский

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METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis

Stem Cells Translational Medicine, Journal Year: 2022, Volume and Issue: 11(9), P. 987 - 1001

Published: Aug. 18, 2022

Abstract The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) main enzyme for N6-methyladenosine (m6A), most prevalent internal modification in mammalian mRNAs, and it has been implicated many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role induction hinders process whose expression decreased both human tissue ovariectomy (OVX) mice. In vivo, METTL14+/− knockdown mice exhibit elevated loss impaired similar to OVX mice, while overexpression significantly promotes formation inhibits progression caused surgery. vitro, enhances osteogenic differentiation ability BMSCs through regulating beclin-1 depending on m6A inducing autophagy; opposite true with silencing. Subsequently, m6A-binding proteins IGF2BP1/2/3 recognize m6A-methylated mRNA promote its translation via mediating RNA stabilization. Furthermore, negatively regulates osteoclast differentiation. Collectively, our study reveals METTL14/IGF2BPs/beclin-1 signal axis highlights roles METTL14-mediated osteoporosis.

Language: Английский

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