scholarly journals The mammalian ULK1 complex and autophagy initiation

2017 ◽  
Vol 61 (6) ◽  
pp. 585-596 ◽  
Author(s):  
Maria Zachari ◽  
Ian G. Ganley
Keyword(s):  
Control Mechanism ◽  
Degradation Pathway ◽  
Autophagosome Formation ◽  
Interacting Protein ◽  
Initial Event ◽  
Protein Partners ◽  
Recycling Pathway ◽  
Quality Control Mechanism ◽  
Cellular Components ◽  
Membrane Organelle

Autophagy is a vital lysosomal degradation pathway that serves as a quality control mechanism. It rids the cell of damaged, toxic or excess cellular components, which if left to persist could be detrimental to the cell. It also serves as a recycling pathway to maintain protein synthesis under starvation conditions. A key initial event in autophagy is formation of the autophagosome, a unique double-membrane organelle that engulfs the cytosolic cargo destined for degradation. This step is mediated by the serine/threonine protein kinase ULK1 (unc-51-like kinase 1), which functions in a complex with at least three protein partners: FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG (autophagy-related protein) 13 (ATG13), and ATG101. In this artcile, we focus on the regulation of the ULK1 complex during autophagy initiation. The complex pattern of upstream pathways that converge on ULK1 suggests that this complex acts as a node, converting multiple signals into autophagosome formation. Here, we review our current understanding of this regulation and in turn discuss what happens downstream, once the ULK1 complex becomes activated.

scholarly journals Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control

2004 ◽  
Vol 165 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Shilpa Vashist ◽  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Control Mechanism ◽  
Degradation Pathway ◽  
Misfolded Proteins ◽  
Er Quality Control ◽  
Golgi Transport ◽  
Test Face ◽  
Folded Proteins ◽  
Quality Control Mechanism

Misfolded proteins retained in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation pathway. The mechanisms used to sort them from correctly folded proteins remain unclear. Analysis of substrates with defined folded and misfolded domains has revealed a system of sequential checkpoints that recognize topologically distinct domains of polypeptides. The first checkpoint examines the cytoplasmic domains of membrane proteins. If a lesion is detected, it is retained statically in the ER and rapidly degraded without regard to the state of its other domains. Proteins passing this test face a second checkpoint that monitors domains localized in the ER lumen. Proteins detected by this pathway are sorted from folded proteins and degraded by a quality control mechanism that requires ER-to-Golgi transport. Although the first checkpoint is obligatorily directed at membrane proteins, the second monitors both soluble and membrane proteins. Our data support a model whereby “properly folded” proteins are defined biologically as survivors that endure a series of distinct checkpoints.

scholarly journals Optineurin mediates delivery of membrane from transferrin receptor-positive endosomes to autophagosomes

2022 ◽  
Author(s):  
Megha Bansal ◽  
Kapil Sirohi ◽  
Shivranjani C Moharir ◽  
Ghanshyam Swarup
Keyword(s):  
Transferrin Receptor ◽  
Control Mechanism ◽  
Adaptor Protein ◽  
Wild Type ◽  
Autophagosome Formation ◽  
Embryonic Fibroblasts ◽  
Over Expression ◽  
Ubiquitin Binding ◽  
Quality Control Mechanism

Autophagy is a conserved quality control mechanism that removes damaged proteins, organelles and invading bacteria through lysosome-mediated degradation. During autophagy several organelles including endoplasmic reticulum, mitochondria, plasma membrane and endosomes contribute membrane for autophagosome formation. However, the mechanisms and proteins involved in membrane delivery to autophagosomes are not clear. Optineurin (OPTN), a cytoplasmic adaptor protein, is involved in promoting maturation of phagophores into autophagosomes; it is also involved in regulating endocytic trafficking and recycling of transferrin receptor (TFRC). Here, we have examined the role of optineurin in the delivery of membrane from TFRC-positive endosomes to autophagosomes. Only a small fraction of autophagosomes was positive for TFRC, indicating that TFRC-positive endosomes could contribute membrane to a subset of autophagosomes. The percentage of TFRC-positive autophagosomes was reduced in Optineurin knockout mouse embryonic fibroblasts (Optn-/-MEFs) in comparison with normal MEFs. Upon over-expression of optineurin, the percentage of TFRC-positive autophagosomes was increased in Optn-/- MEFs. Unlike wild-type optineurin, a disease-associated mutant, E478G, defective in ubiquitin binding, was not able to enhance formation of TFRC-positive autophagosomes in Optn-/- MEFs. TFRC degradation mediated by autophagy was decreased in optineurin deficient cells. Our results suggest that optineurin mediates delivery of TFRC and perhaps associated membrane from TFRC-positive endosomes to autophagosomes, and this may contribute to autophagosome formation.

scholarly journals Role of skeletal muscle autophagy in high-fat-diet–induced obesity and exercise

2019 ◽  
Vol 78 (1) ◽  
pp. 56-64
Author(s):  
Adrienne R Herrenbruck ◽  
Lance M Bollinger
Keyword(s):  
Skeletal Muscle ◽  
High Fat Diet ◽  
Control Mechanism ◽  
Degradation Pathway ◽  
The Body ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Quality Control Mechanism ◽  
The Impact

Abstract Autophagy is a complex degradation pathway responsible for clearing damaged and dysfunctional organelles. High-fat-diet–induced obesity has been shown to alter autophagy throughout the body in a tissue-specific manner. The impact of obesity on skeletal muscle autophagy has yet to be elucidated. This review examines the impact of high-fat-diet–induced obesity and exercise on skeletal muscle autophagy. Better understanding this major quality control mechanism may help develop novel therapies to combat high-fat-diet–induced obesity comorbidities.

scholarly journals Quality-Control Mechanism for Telomerase RNA Folding in the Cell

Cell Reports ◽  
2020 ◽  
Vol 33 (13) ◽  
pp. 108568
Author(s):  
Xichan Hu ◽  
Jin-Kwang Kim ◽  
Clinton Yu ◽  
Hyun-Ik Jun ◽  
Jinqiang Liu ◽  
...  
Keyword(s):  
Quality Control ◽  
Rna Folding ◽  
Control Mechanism ◽  
Telomerase Rna ◽  
Quality Control Mechanism

scholarly journals Modulating mitochondrial quality in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children

2016 ◽  
Vol 44 (4) ◽  
pp. 1091-1100 ◽  
Author(s):  
Alan Diot ◽  
Eszter Dombi ◽  
Tiffany Lodge ◽  
Chunyan Liao ◽  
Karl Morten ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Disease Transmission ◽  
Stochastic Dynamics ◽  
Genetic Diagnosis ◽  
Healthy Children ◽  
Non Invasive ◽  
Incurable Disease ◽  
Mitochondrial Replacement Therapy ◽  
Quality Control Mechanism ◽  
Cellular Components

One in 400 people has a maternally inherited mutation in mtDNA potentially causing incurable disease. In so-called heteroplasmic disease, mutant and normal mtDNA co-exist in the cells of carrier women. Disease severity depends on the proportion of inherited abnormal mtDNA molecules. Families who have had a child die of severe, maternally inherited mtDNA disease need reliable information on the risk of recurrence in future pregnancies. However, prenatal diagnosis and even estimates of risk are fraught with uncertainty because of the complex and stochastic dynamics of heteroplasmy. These complications include an mtDNA bottleneck, whereby hard-to-predict fluctuations in the proportions of mutant and normal mtDNA may arise between generations. In ‘mitochondrial replacement therapy’ (MRT), damaged mitochondria are replaced with healthy ones in early human development, using nuclear transfer. We are developing non-invasive alternatives, notably activating autophagy, a cellular quality control mechanism, in which damaged cellular components are engulfed by autophagosomes. This approach could be used in combination with MRT or with the regular management, pre-implantation genetic diagnosis (PGD). Mathematical theory, supported by recent experiments, suggests that this strategy may be fruitful in controlling heteroplasmy. Using mice that are transgenic for fluorescent LC3 (the hallmark of autophagy) we quantified autophagosomes in cleavage stage embryos. We confirmed that the autophagosome count peaks in four-cell embryos and this correlates with a drop in the mtDNA content of the whole embryo. This suggests removal by mitophagy (mitochondria-specific autophagy). We suggest that modulating heteroplasmy by activating mitophagy may be a useful complement to mitochondrial replacement therapy.

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