Optineurin provides a mitophagy contact site for TBK1 activation

The EMBO Journal, Год журнала: 2024, Номер 43(5), С. 754 - 779

Опубликована: Янв. 29, 2024

Abstract Tank-binding kinase 1 (TBK1) is a Ser/Thr that involved in many intracellular processes, such as innate immunity, cell cycle, and apoptosis. TBK1 also important for phosphorylating the autophagy adaptors mediate selective autophagic removal of damaged mitochondria. However, mechanism by which PINK1-Parkin-mediated mitophagy activates remains largely unknown. Here, we show adaptor optineurin (OPTN) provides unique platform activation. Both OPTN-ubiquitin OPTN-pre-autophagosomal structure (PAS) interaction axes facilitate assembly OPTN-TBK1 complex at contact sites between mitochondria autophagosome formation sites. At this point, positive feedback loop activation initiated accelerates hetero-autophosphorylation protein. Expression monobodies engineered here to bind OPTN impaired accumulation sites, well subsequent TBK1, thereby inhibiting mitochondrial degradation. Taken together, these data reciprocal relationship initiates biogenesis on

Язык: Английский

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Targeted protein degradation directly engaging lysosomes or proteasomes

Chemical Society Reviews, Год журнала: 2024, Номер 53(7), С. 3253 - 3272

Опубликована: Янв. 1, 2024

This review delineates emerging technologies for targeted protein degradation that directly involve lysosomes or proteasomes. It explores their unique features, advantages, and limitations, offering perspectives on future therapeutic applications.

Язык: Английский

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The Role of ATG9 Vesicles in Autophagosome Biogenesis

Journal of Molecular Biology, Год журнала: 2024, Номер 436(15), С. 168489 - 168489

Опубликована: Фев. 10, 2024

Autophagy mediates the degradation and recycling of cellular material in lysosomal system. Dysfunctional autophagy is associated with a plethora diseases including uncontrolled infections, cancer neurodegeneration. In macroautophagy (hereafter autophagy) this encapsulated double membrane vesicles, autophagosomes, which form upon induction autophagy. The precursors to referred as phagophores, first appear small flattened cisternae, gradually enclose cargo they grow. assembly phagophores during initiation has been major subject investigation over past decades. A special focus ATG9, only conserved transmembrane protein among core machinery. majority ATG9 localizes Golgi-derived vesicles. Here we review recent advances breakthroughs regarding our understanding how vesicles it resides serve assemble machinery establish contact sites for autophagosome biogenesis. We also highlight open questions field that need be addressed years come.

Язык: Английский

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Neuronal Autophagy: Regulations and Implications in Health and Disease

Cells, Год журнала: 2024, Номер 13(1), С. 103 - 103

Опубликована: Янв. 4, 2024

Autophagy is a major degradative pathway that plays key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed double-membrane autophagosome fuses with lysosomes, orchestrated by complex cascade events. has particularly strong impact on nervous system, mutations core cause numerous neurological diseases. We first review regulation autophagy, from biogenesis to lysosomal degradation associated neurodevelopmental/neurodegenerative disorders. then describe how this process specifically regulated axon somatodendritic compartment it altered In particular, we present neuronal specificities spatial control biogenesis, close relationship maturation axonal transport, synaptic activity. Finally, discuss functions autophagy during development adulthood.

Язык: Английский

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Aggrephagy at a glance

Journal of Cell Science, Год журнала: 2023, Номер 136(10)

Опубликована: Май 15, 2023

ABSTRACT Cells keep their proteome functional by the action of proteostasis network, composed chaperones, ubiquitin-proteasome system and autophagy. The decline this network results in accumulation protein aggregates is associated with aging disease. In Cell Science at a Glance accompanying poster, we provide an overview molecular mechanisms removal selective autophagy pathway, termed aggrephagy. We outline how aggrephagy regulated post-translational modifications via auxiliary proteins. further describe alternative pathways physiology disruption pathology. particular, discuss neurons wide range diseases. Finally, highlight strategies to reprogram treat aggregation

Язык: Английский

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Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD

Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(11), С. 1717 - 1731

Опубликована: Июнь 25, 2024

Abstract Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding 1) adaptors NAP1 (NAK-associated protein SINTBAD (similar to adaptor) restrict initiation of OPTN (optineurin)-driven competing with TBK1. Conversely, they promote nuclear dot 52 (NDP52)-driven recruiting NDP52 stabilizing its interaction FIP200. Notably, emerges as primary recruiter during initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define cargo receptor rheostats, elevating threshold promoting pathway set motion supporting NDP52. These findings shed light on cellular strategy hyperactivity still efficient progression.

Язык: Английский

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Molecular Mechanism of Autophagosome–Lysosome Fusion in Mammalian Cells

Cells, Год журнала: 2024, Номер 13(6), С. 500 - 500

Опубликована: Март 13, 2024

In eukaryotes, targeting intracellular components for lysosomal degradation by autophagy represents a catabolic process that evolutionarily regulates cellular homeostasis. The successful completion of initiates the engulfment cytoplasmic materials within double-membrane autophagosomes and subsequent delivery to autolysosomes acidic proteases. formation relies on precise fusion with lysosomes. recent decades, numerous studies have provided insights into molecular regulation autophagosome–lysosome fusion. this review, an overview molecules function in lysosomes is provided. Moreover, mechanism underlying how these functional regulate summarized.

Язык: Английский

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A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy

The Journal of Cell Biology, Год журнала: 2024, Номер 223(7)

Опубликована: Апрель 6, 2024

Activation of PINK1 and Parkin in response to mitochondrial damage initiates a that includes phosphorylation RAB7A at Ser72. Rubicon is binding negative regulator autophagy. The structure the Rubicon:RAB7A complex suggests Ser72 would block binding. Indeed, vitro by TBK1 abrogates Pacer, positive autophagy, has an RH domain with basic triad predicted bind introduced phosphate. Consistent this, Pacer-RH binds phosho-RAB7A but not unphosphorylated RAB7A. In cells, depolarization reduces colocalization whilst recruiting Pacer phospho-RAB7A–positive puncta. knockout mitophagy little effect on bulk autophagy or Parkin-independent mitophagy. Rescue Parkin-dependent requires intact pRAB7A phosphate-binding Pacer. Together these structural functional data support model which TBK1-dependent serves as switch, promoting relieving inhibition favoring activation.

Язык: Английский

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Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery

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

Опубликована: Авг. 28, 2024

Selective autophagy is a lysosomal degradation pathway that critical for maintaining cellular homeostasis by disposing of harmful material. While the mechanisms which soluble cargo receptors recruit machinery are becoming increasingly clear, principles governing how organelle-localized transmembrane initiate selective remain poorly understood. Here, we demonstrate can autophagosome biogenesis not only recruiting upstream FIP200/ULK1 complex but also via WIPI-ATG13 complex. This latter employed BNIP3/NIX to trigger mitophagy. Additionally, other mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use complex, while FKBP8 ER-phagy receptor TEX264 capable utilizing both pathways autophagy. Our study defines molecular rules initiation revealing remarkable flexibility in assembly activation machinery, with significant implications therapeutic interventions.

Язык: Английский

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Physiological functions of ULK1/2

Journal of Molecular Biology, Год журнала: 2024, Номер 436(15), С. 168472 - 168472

Опубликована: Фев. 2, 2024

UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine that best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR AMPK relay them to downstream components machinery. also play indispensable roles selective pathway, removing damaged mitochondria, invading pathogens, toxic protein aggregates. Additional functions have emerged beyond autophagy, including trafficking, RNP granule dynamics, signaling events impacting innate immunity, axon guidance, homeostasis, cell fate. Therefore, it is no surprise alterations expression activity been linked with pathophysiological processes, cancer, neurological disorders, cardiovascular diseases. Growing evidence suggests function biological rheostats, tuning intra extra-cellular cues. Given broad physiological relevance, candidate targets small molecule activators or inhibitors may pave way development therapeutics treatment diseases humans.

Язык: Английский

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