Emerging degrader technologies engaging lysosomal pathways

Chemical Society Reviews, Год журнала: 2022, Номер 51(21), С. 8832 - 8876

Опубликована: Янв. 1, 2022

ATTECs and several other emerging degrader technologies hijacking the lysosomal pathways greatly expand spectrum of degradable targets provide new opportunities for targeted drug discovery.

Язык: Английский

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Orchestration of selective autophagy by cargo receptors

Current Biology, Год журнала: 2022, Номер 32(24), С. R1357 - R1371

Опубликована: Дек. 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.

Язык: Английский

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ER as master regulator of membrane trafficking and organelle function

The Journal of Cell Biology, Год журнала: 2022, Номер 221(10)

Опубликована: Авг. 23, 2022

The endoplasmic reticulum (ER), which occupies a large portion of the cytoplasm, is cell’s main site for biosynthesis lipids and carbohydrate conjugates, it essential folding, assembly, biosynthetic transport secreted proteins integral membrane proteins. discovery abundant contact sites (MCSs) between ER other compartments has revealed that, in addition to its secretory functions, plays key roles regulation organelle dynamics functions. In this review, we will discuss how regulates endosomes, lysosomes, autophagosomes, mitochondria, peroxisomes, Golgi apparatus via MCSs. Such occurs lipid Ca2+ transfer also control trans dephosphorylation reactions motility, positioning, fusion, fission. diverse controls organelles MCSs manifest as master regulator biology.

Язык: Английский

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In situ structural analysis reveals membrane shape transitions during autophagosome formation

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(39)

Опубликована: Сен. 19, 2022

Autophagosomes are unique organelles that form de novo as double-membrane vesicles engulfing cytosolic material for destruction. Their biogenesis involves membrane transformations of distinctly shaped intermediates whose ultrastructure is poorly understood. Here, we combine cell biology, correlative cryo-electron tomography (cryo-ET), and extensive data analysis to reveal the step-by-step structural progression autophagosome at high resolution directly within yeast cells. The uncovers an unexpectedly thin intermembrane distance dilated phagophore rim. Mapping individual autophagic structures onto a timeline based on geometric features reveals dynamical change shape curvature in growing phagophores. Moreover, our tomograms show organelle interactome autophagosomes, highlighting polar organization contact sites between organelles, such vacuole endoplasmic reticulum (ER). Collectively, these findings have important implications contribution different sources during autophagy forces shaping driving phagophores toward closure without templating cargo.

Язык: Английский

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Recent advances in targeting autophagy in cancer

Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(5), С. 290 - 302

Опубликована: Март 15, 2023

Язык: Английский

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Unconventional initiation of PINK1/Parkin mitophagy by Optineurin

Molecular Cell, Год журнала: 2023, Номер 83(10), С. 1693 - 1709.e9

Опубликована: Май 1, 2023

Cargo sequestration is a fundamental step of selective autophagy in which cells generate double-membrane structure termed an "autophagosome" on the surface cargoes. NDP52, TAX1BP1, and p62 bind FIP200, recruits ULK1/2 complex to initiate autophagosome formation How OPTN initiates during remains unknown despite its importance neurodegeneration. Here, we uncover unconventional path PINK1/Parkin mitophagy initiation by that does not begin with FIP200 binding or require kinases. Using gene-edited cell lines vitro reconstitutions, show utilizes kinase TBK1, binds directly class III phosphatidylinositol 3-kinase I mitophagy. During NDP52 initiation, TBK1 functionally redundant ULK1/2, classifying TBK1's role as autophagy-initiating kinase. Overall, this work reveals mechanistically distinct highlights mechanistic plasticity pathways.

Язык: Английский

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RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions

Annual Review of Cell and Developmental Biology, Год журнала: 2023, Номер 39(1), С. 409 - 434

Опубликована: Июль 5, 2023

The life of eukaryotic cells requires the transport lipids between membranes, which are separated by aqueous environment cytosol. Vesicle-mediated traffic along secretory and endocytic pathways lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few at time thought mediate shuttle-like mechanisms. Over last years, new family has been discovered that is defined repeating β-groove (RBG) rod-like structure with hydrophobic channel running their entire length. This localization these membrane contact sites suggest bridge-like mechanism Mutations some result neurodegenerative developmental disorders. Here we review properties well-established putative physiological roles proteins, highlight many questions remain open about functions.

Язык: Английский

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Liquid–liquid phase separation in autophagy

The Journal of Cell Biology, Год журнала: 2020, Номер 219(8)

Опубликована: Июнь 30, 2020

Liquid–liquid phase separation (LLPS) compartmentalizes and concentrates biomacromolecules into distinct condensates. Liquid-like condensates can transition gel solid states, which are essential for fulfilling their different functions. LLPS plays important roles in multiple steps of autophagy, mediating the assembly autophagosome formation sites, acting as an unconventional modulator TORC1-mediated autophagy regulation, triaging protein cargos degradation. Gel-like, but not solid, trigger surrounding autophagosomal membranes. Stress pathological conditions cause aberrant condensates, evade surveillance by machinery. Understanding mechanisms underlying will provide potential therapeutic targets aggregation diseases.

Язык: Английский

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Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation

Developmental Cell, Год журнала: 2019, Номер 49(1), С. 130 - 144.e6

Опубликована: Фев. 28, 2019

Язык: Английский

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Sealing holes in cellular membranes

The EMBO Journal, Год журнала: 2021, Номер 40(7)

Опубликована: Март 1, 2021

The compartmentalization of eukaryotic cells, which is essential for their viability and functions, ensured by single or double bilayer membranes that separate the cell from exterior form boundaries between cell's organelles cytosol. Nascent nuclear envelopes autophagosomes, both are enveloped membranes, need to be sealed during late stage biogenesis. On other hand, integrity cellular such as plasma membrane, lysosomes envelope can compromised pathogens, chemicals, radiation, inflammatory responses mechanical stress. There programmes restore membrane after injury. Here, we review mechanisms have evolved maintain organelle biogenesis injury, including scission mediated endosomal sorting complex required transport (ESCRT), vesicle patching endocytosis.

Язык: Английский

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