Wetting regulates autophagy of phase-separated compartments and the cytosol

Agudo-Canalejo, Jaime; Schultz, Sebastian W.; Chino, Haruo; Migliano, Simona M.; Saito, Chieko; Koyama-Honda, Ikuko; Stenmark, Harald; Brech, Andreas; May, Alexander I.; Mizushima, Noboru; Knorr, Roland L.

doi:10.1038/s41586-020-2992-3

Cited by 176 publications

(164 citation statements)

References 52 publications

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“…Our results are fully in agreement with another recent report showing that p62-LC3 interaction on the p62-droplets controls the direction of autophagosome formation. 8 Our results further demonstrated that p62-gels play a central role in oxidative stress response. Nuclear factor erythroid 2-related factor 2 (NRF2) is a basic leucine zipper (bZIP) transcription factor, and its heterodimer with small musculoaponeurotic fibrosarcoma (MAF) proteins controls the expression of proteins that protect against oxidative damage triggered by injury and inflammation.…”

supporting

confidence: 70%

p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control

Eskelinen

Kageyama

Komatsu

2021

Molecular & Cellular Oncology

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Selective autophagy contributes to the degradation of condensates, such as sequestosome 1-bodies, also called p62/SQSTM1-bodies. We showed that endogenous p62 forms gel-like structures, which serve as platforms for autophagosome formation and nuclear factor erythroid 2-related factor 2 (NRF2) activation. Further, p62-mediated NRF2 activation is not cytotoxic, but combination of NRF2 activation with impaired bulk and selective autophagy causes liver injury.

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supporting

confidence: 70%

p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control

Eskelinen

Kageyama

Komatsu

2021

Molecular & Cellular Oncology

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“…While changes in condensate viscosity often have pathological consequences, the surface tension of biomolecular condensates can play key physiological roles: differences in surface tension can lead to layered multi-phase condensates, such as the compartmentation in nucleoli 12–14 . During autophagy, surface tension determines whether p62 condensates will be sequestered in small droplets or digested as a whole 15 . Finally, the nucleation of microtubule branches relies on an instability of TPX2 condensates, driven solely by the condensates’ surface tension 16 .…”

Section: Main Textmentioning

confidence: 99%

“…To calibrate ‘ M ’ with liquids that are appropriate for MPA (Figure 1), we chose an ATPS composed of PEG (8000 Da) and dextran (500,000 Da) 15,29,32 . Under a range of concentrations, mixtures of PEG and dextran will phase-separate into emulsions of micrometer-size droplets (Figure S1a).…”

Section: Main Textmentioning

confidence: 99%

“…Many proteins tend to wet and adsorb onto solid surfaces 4,16,23,24,34 . While potentially mediating important biological processes 15,16,34 , this wetting effect can introduce significant artifacts in measurements that rely on the fusion kinetics or morphology of condensates 12,23,24 . In contrast, the contribution of R c in eq.…”

Section: Main Textmentioning

confidence: 99%

“…RGG condensates fuse quickly (~0.1 s) with >90% of the constituting proteins moving freely, consistent with their liquid behavior during MPA. However, many biomolecular condensates can take more than 100 s to fuse 15,36 , while exhibiting small fractions (<50%) of mobile proteins 3,10,37,38 . In the latter cases, MPA measurements will be essential to clarify confusion around the condensates’ material properties 10 .…”

Section: Main Textmentioning

confidence: 99%

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More than just oil droplets in water: surface tension and viscosity of protein condensates quantified by micropipette aspiration

Wang

Milovanović

et al. 2021

Preprint

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The material properties of biomolecular condensates play pivotal roles in many biological and pathological processes. Despite the rapid increase in the number of biomolecules identified that undergo liquid-liquid phase separation (LLPS), quantitative studies of the resulting condensates have been severely lagging behind. Here, we develop a micropipette-based technique, which uniquely allows quantifications of both the surface tension and viscosity of biomolecular condensates, independent of labeling and surface wetting effects. We demonstrate the accuracy and versatility of this technique by measuring condensates of LAF-1 RGG domains and a polymer-based aqueous two-phase system (ATPS). We anticipate this technique will be widely applicable to biomolecular condensates and will resolve several limitations regarding current approaches.

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Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis

et al. 2023

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Autophagy is a highly conserved intracellular pathway that is essential for survival in all eukaryotes. In healthy cells, autophagy is used to remove damaged intracellular components, which can be as simple as unfolded proteins or as complex as whole mitochondria. Once the damaged component is captured, the autophagosome engulfs it and closes, isolating the content from the cytoplasm. The autophagosome then fuses with the late endosome and/or lysosome to deliver its content to the lysosome for degradation. Formation of the autophagosome, sequestration or capture of content, and closure all require the ATG proteins, which constitute the essential core autophagy protein machinery. This brief ‘nutshell’ will highlight recent data revealing the importance of small membrane‐associated domains in the ATG proteins. In particular, recent findings from two parallel studies reveal the unexpected key role of α‐helical structures in the ATG8 conjugation machinery and ATG8s. These studies illustrate how unique membrane association modules can control the formation of autophagosomes.

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Wetting regulates autophagy of phase-separated compartments and the cytosol

Cited by 176 publications

References 52 publications

p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control

p62/SQSTM1 droplets initiate autophagosome biogenesis and oxidative stress control

More than just oil droplets in water: surface tension and viscosity of protein condensates quantified by micropipette aspiration

Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis

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