Cellular quality control by the ubiquitin-proteasome system and autophagy

Pohl, Christian; Đikić, Ivan

doi:10.1126/science.aax3769

Cited by 796 publications

(583 citation statements)

References 44 publications

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“…Research in the last decade has transformed autophagy from a bulk degradation system to a highly selective cellular quality control pathway that rapidly removes toxic or superfluous macromolecules 28,29 . Especially organelles that get damaged due to metabolic and physiological stress conditions are mainly recycled via distinct selective autophagy pathways 6 .…”

Section: Discussionmentioning

confidence: 99%

Friendly regulates membrane depolarization induced mitophagy in Arabidopsis

Liang

Zhao

et al. 2020

Preprint

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The oxidative environment within the mitochondria makes them particularly vulnerable to proteotoxic stress. To maintain a healthy mitochondrial network, eukaryotes have evolved multi-tiered quality control pathways. If the stress cannot be alleviated, defective mitochondria are selectively removed by autophagy via a process termed mitophagy. Despite significant advances in metazoans and yeast, in plants, the molecular underpinnings of mitophagy are largely unknown. Here, using time-lapse imaging, electron tomography and biochemical assays, we show that uncoupler treatments cause loss of mitochondrial membrane potential and induce autophagy in Arabidopsis. The damaged mitochondria are selectively engulfed by autophagosomes that are ATG5 dependent and labelled by ATG8 proteins. Friendly, a member of the Clustered Mitochondria protein family, is recruited to the damaged mitochondria to mediate mitophagy. In addition to stress, mitophagy is also induced during de-etiolation, a major cellular transformation during photomorphogenesis that involves chloroplast maturation. De-etiolation triggered mitophagy regulates cotyledon greening, pointing towards an inter-organellar cross-talk mechanism. Altogether our results demonstrate how plants employ mitophagy to recycle damaged mitochondria during stress and development.

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Section: Discussionmentioning

confidence: 99%

Friendly regulates membrane depolarization induced mitophagy in Arabidopsis

Liang

Zhao

et al. 2020

Preprint

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“…In parallel, a significant number of ubiquitin/proteasome-associated proteins were brought back to near control levels. Considering that both the ubiquitin/proteasome system and autophagy share multiple molecular determinants, including ULK1, ATG5, ATG8 and p62, which can be simultaneously and mutually affected in neurodegenerative diseases [83,84], it becomes evident that BX795 helps misfolded protein clearance by limiting protein synthesis. This is in agreement with its demonstrated ability to decrease protein aggregates in p.A53T-neurons, as shown in this study, along with facilitation of autophagy in SYSH-5Y cells expressing p.A53T.…”

Section: Discussionmentioning

confidence: 99%

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

Antoniou

Prodromidou

Kouroupi

et al. 2020

Preprint

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Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)based disease models represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson's disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores diseaseassociated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the neuroprotective effects of BX795 that comprised a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuron-like cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have developed an adaptable platform based on p.A53T iPSC-derived neurons for drug screening and identified a promising small molecule with potent neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.3 Key words α-synuclein, p.A53T α-synuclein mutation, induced pluripotent stem cell derived neurons, drug screening, mTOR signaling, mRNA metabolism, proteostasis AcknowledgementsWe thank Drs. Tamotsu Yoshimori and Terje Johansen for providing GFP-LC3 and mChery-GFP-p62 plasmids, respectively.

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“…The site of linkage destines the modified protein to different functions. For example, poly-ubiquitination through the lysines at position 11 and 48 typically lead to degradation of the protein through the 26S proteasome [77,78].…”

Section: Ubiquitination and Lipidationmentioning

confidence: 99%

Post-translational modifications and stress adaptation: the paradigm of FKBP51

Rein

2020

Biochemical Society Transactions

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Adaptation to stress is a fundamental requirement to cope with changing environmental conditions that pose a threat to the homeostasis of cells and organisms. Post-translational modifications (PTMs) of proteins represent a possibility to quickly produce proteins with new features demanding relatively little cellular resources. FK506 binding protein (FKBP) 51 is a pivotal stress protein that is involved in the regulation of several executers of PTMs. This mini-review discusses the role of FKBP51 in the function of proteins responsible for setting the phosphorylation, ubiquitination and lipidation of other proteins. Examples include the kinases Akt1, CDK5 and GSK3β, the phosphatases calcineurin, PP2A and PHLPP, and the ubiquitin E3-ligase SKP2. The impact of FKBP51 on PTMs of signal transduction proteins significantly extends the functional versatility of this protein.As a stress-induced protein, FKBP51 uses re-setting of PTMs to relay the effect of stress on various signaling pathways.

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Cellular quality control by the ubiquitin-proteasome system and autophagy

Cited by 796 publications

References 44 publications

Friendly regulates membrane depolarization induced mitophagy in Arabidopsis

Friendly regulates membrane depolarization induced mitophagy in Arabidopsis

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

Post-translational modifications and stress adaptation: the paradigm of FKBP51

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