scholarly journals Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy

2012 ◽  
Vol 2012 ◽  
pp. 1-21 ◽  
Author(s):  
Trond Lamark ◽  
Terje Johansen
Keyword(s):  
Protein Aggregation ◽  
Continuous Process ◽  
Protein Aggregates ◽  
Aggregate Formation ◽  
Selective Degradation ◽  
Chaperone Mediated Autophagy ◽  
Single Peptide

Protein aggregation is a continuous process in our cells. Some proteins aggregate in a regulated manner required for different vital functional processes in the cells whereas other protein aggregates result from misfolding caused by various stressors. The decision to form an aggregate is largely made by chaperones and chaperone-assisted proteins. Proteins that are damaged beyond repair are degraded either by the proteasome or by the lysosome via autophagy. The aggregates can be degraded by the proteasome and by chaperone-mediated autophagy only after dissolution into soluble single peptide species. Hence, protein aggregates as such are degraded by macroautophagy. The selective degradation of protein aggregates by macroautophagy is called aggrephagy. Here we review the processes of aggregate formation, recognition, transport, and sequestration into autophagosomes by autophagy receptors and the role of aggrephagy in different protein aggregation diseases.

scholarly journals The Role of Chaperone-Mediated Autophagy in Hepatitis C Virus-Induced Pathogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Chieko Matsui ◽  
Putu Yuliandari ◽  
Lin Deng ◽  
Takayuki Abe ◽  
Ikuo Shoji
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Degradation Process ◽  
Degradation Pathway ◽  
Hepatocyte Nuclear Factor ◽  
Selective Degradation ◽  
Substrate Protein ◽  
Hepatocyte Nuclear Factor 1Α ◽  
Chaperone Mediated Autophagy

Lysosome incorporate and degrade proteins in a process known as autophagy. There are three types of autophagy; macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Although autophagy is considered a nonselective degradation process, CMA is known as a selective degradation pathway. All proteins internalized in the lysosome via CMA contain a pentapeptide KFERQ-motif, also known as a CMA-targeting motif, which is necessary for selectivity. CMA directly delivers a substrate protein into the lysosome lumen using the cytosolic chaperone HSC70 and the lysosomal receptor LAMP-2A for degradation. Hepatitis C virus (HCV) NS5A protein interacts with hepatocyte-nuclear factor 1α (HNF-1α) together with HSC70 and promotes the lysosomal degradation of HNF-1α via CMA, resulting in HCV-induced pathogenesis. HCV NS5A promotes recruitment of HSC70 to the substrate protein HNF-1α. HCV NS5A plays a crucial role in HCV-induced CMA. Further investigations of HCV NS5A-interacting proteins containing CMA-targeting motifs may help to elucidate HCV-induced pathogenesis.

scholarly journals Intercellular Spread of Protein Aggregates in Neurodegenerative Disease

2018 ◽  
Vol 34 (1) ◽  
pp. 545-568 ◽  
Author(s):  
Albert A. Davis ◽  
Cheryl E.G. Leyns ◽  
David M. Holtzman
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Extracellular Space ◽  
Protein Aggregates ◽  
Therapeutic Strategies ◽  
Disease Pathogenesis ◽  
Donor Cells ◽  
Intercellular Spread

Most neurodegenerative diseases are characterized by the accumulation of protein aggregates, some of which are toxic to cells. Mounting evidence demonstrates that in several diseases, protein aggregates can pass from neuron to neuron along connected networks, although the role of this spreading phenomenon in disease pathogenesis is not completely understood. Here we briefly review the molecular and histopathological features of protein aggregation in neurodegenerative disease, we summarize the evidence for release of proteins from donor cells into the extracellular space, and we highlight some other mechanisms by which protein aggregates might be transmitted to recipient cells. We also discuss the evidence that supports a role for spreading of protein aggregates in neurodegenerative disease pathogenesis and some limitations of this model. Finally, we consider potential therapeutic strategies to target spreading of protein aggregates in the treatment of neurodegenerative diseases.

scholarly journals Mitochondrial fission facilitates the selective mitophagy of protein aggregates

2017 ◽  
Vol 216 (10) ◽  
pp. 3231-3247 ◽  
Author(s):  
Jonathon L. Burman ◽  
Sarah Pickles ◽  
Chunxin Wang ◽  
Shiori Sekine ◽  
Jose Norberto S. Vargas ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Matrix Protein ◽  
Mitochondrial Fission ◽  
Protein Aggregates ◽  
Mitochondrial Matrix ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Networks ◽  
Mitochondrial Unfolded Protein Response

Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1–Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing ΔOTC, it does not decrease the rate of ΔOTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for ΔOTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1–Parkin activity.

scholarly journals Reversion of protein aggregation mediated by Sso7d in cell extracts of Sulfolobus solfataricus

2004 ◽  
Vol 381 (1) ◽  
pp. 249-255 ◽  
Author(s):  
Annamaria GUAGLIARDI ◽  
Lucia MANCUSI ◽  
Mosè ROSSI
Keyword(s):  
Escherichia Coli ◽  
Protein Aggregation ◽  
Atp Hydrolysis ◽  
Sulfolobus Solfataricus ◽  
Protein Aggregates ◽  
Eukaryotic Cells ◽  
Cell Extracts ◽  
Thermophilic Archaeon

In eukaryotic cells and in Escherichia coli, reversion of protein aggregation is mediated by the network of chaperones belonging to Hsp70 and Hsp100 families [Weibezahn, Bukau and Mogk (2004) Microb. Cell Fact. 3, 1–12]. The thermophilic prokaryotes of the archaea domain lack homologues of these chaperone families, and the mechanisms they use to rescue aggregated proteins are unknown [Macario, Malz and Conway de Macario (2004) Front. Biosci. 9, 1318–1332]. In the present study, we show that stable protein aggregates can be detected in extracts of starved cells of the thermophilic archaeon Sulfolobus solfataricus, and that the protein Sso7d interacts with the aggregates and mediates the disassembly of the aggregates and the re-activation of insolubilized β-glycosidase in the presence of ATP hydrolysis. Furthermore, we report that heat-induced protein aggregates in extracts of exponential cells of S. solfataricus contain Sso7d that rescues insolubilized proteins in the presence of ATP hydrolysis. Results of these experiments performed in cell extracts are consistent with an in vivo role of Sso7d in reverting protein aggregation.

scholarly journals Optineurin promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates

2020 ◽  
Author(s):  
Shivranjani C Moharir ◽  
Akhouri Kishore Raghawan ◽  
Ghanshyam Swarup
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neuronal Cells ◽  
Protein Aggregates ◽  
Mutant Protein ◽  
Mutant Huntingtin ◽  
Aggregate Formation ◽  
Wild Type ◽  
Mutant Proteins

AbstractOptineurin (OPTN), a cytoplasmic adaptor protein involved in cargo selective autophagy of bacteria, damaged mitochondria and mutant protein aggregates, is frequently seen in pathological structures containing protein aggregates, associated with several neurodegenerative diseases. However, the function of OPTN in these protein aggregates is not known. Here, we have explored the role of OPTN in mutant protein aggregation and in cytoprotection from toxicity of mutant proteins. Mutant huntingtin (mHtt) and mutant ataxin-3 (mAtax-3) showed reduced formation of aggregates in Optn−/− mouse embryonic fibroblasts as compared with wild type cells. Co-expression of OPTN enhanced aggregate formation by mHtt and mAtax-3 in Optn−/− cells. C-terminal domain of OPTN (412-577 amino acids) was necessary and sufficient to promote aggregate formation by these mutant proteins. The E478G mutant of OPTN, defective in ubiquitin-binding and autophagy, was also able to promote aggregation of mHtt and mAtax-3. OPTN and its C-terminal domain form a complex with the chaperone HSP70 known to promote mutant protein aggregation. Overexpression of mHtt or mAtax-3 induced more cell death in Optn−/− cells compared with wild type cells. Importantly, compared to wild type cells, Optn-deficient cells having mHtt or mAtax-3 aggregates showed higher level of cell death in neuronal (N2A) and non-neuronal cells. Our results show that OPTN promotes formation of mutant huntingtin and mutant ataxin-3 aggregates, and this function of OPTN might be mediated through interaction with HSP70 chaperones. Our results also show that OPTN reduces cytotoxicity caused by these mutant protein aggregates.Significance statementThe hallmark of several neurodegenerative diseases like amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and Pick’s disease is the formation of pathological structures containing aggregated proteins, and OPTN is frequently observed in these structures. What role optineurin plays in those aggregates is not clear. Our results show that OPTN promotes aggregation of mutant huntingtin and mutant ataxin-3, and reduces cytotoxicity of aggregates in neuronal and non-neuronal cells. We suggest that OPTN provides cytoprotection in three different ways-by promoting mutant protein aggregation, by reducing cytotoxicity of aggregates and by autophagy-dependent clearance of aggregates reported earlier. These properties of OPTN provide a possible explanation for its association with various pathological structures containing protein aggregates seen in several neurodegenerative diseases.

Abstract 393: The Intercalated Disc Protein Myozap: A Novel Player in Cardiac Proteinopathy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ashraf Y Rangrez ◽  
Derk Frank ◽  
Liam Cassidy ◽  
Lynn Christen ◽  
Inka Geurink ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Protein Aggregation ◽  
Protein Quality ◽  
Transcriptome Profiling ◽  
Protein Aggregates ◽  
Intercalated Disc ◽  
Protein Aggregate ◽  
General Role ◽  
Id Protein

Background: A growing number of cardiac muscle diseases are characterized by depositions of misfolded proteins, including cardiac amyloidosis and desmin-releated cardiomyopathy (DRM). The continued presence and chronic accumulation of misfolded or unfolded proteins can lead to aggregation and/or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitates a downward spiral of the cell’s ability to maintain homeostasis and may eventually result in cell death. We recently identified massive protein aggregates in the hearts of transgenic mice overexpressing the intercalated disc (ID) protein myozap (Myozap-tg). We now sought to investigate the precise composition of these aggregates and the role of Myozap in other proteinopathies such as DRM. Methods and Results: We employed multi-dimensional proteomics, transcriptomics, confocal microscopy, and molecular biology approaches to decipher the underlying causes and consequences of protein aggregate formation in Myozap-tg mice. Transcriptome profiling of these mice revealed striking upregulation of autophagy, protein synthesis, and pro-inflammatory pathways, whereas protein degradation pathways were down-regulated. Surprisingly, proteomics analyses revealed Desmin and α-crystallin B (CryAB) as the major constituents of the aggregates, which was further validated by confocal microscopy. Moreover, we identified the presence of toxic preamyloid oligomers in Myozap-tg mouse hearts, a hallmark in many protein aggregation-based diseases including DRM. Most interestingly, we also observed co-localization of Myozap with protein aggregates observed in both transgenic mouse hearts overexpressing mutant Desmin (D7) and mutant CryAB (R120G), as well as in human DRM patients. Conclusion: The present study implies a new role for Myozap, which was previously reported to affect cardiac SRF signaling: (1) Myozap accumulates in various forms of experimental and human protein aggregation cardiomyopathy, suggesting involvement in protein homoestasis. (2) The fact that Myozap is now the third ID protein (after desmin and CryAB) to cause cardiac proteinopathy points to a general role of the ID in its molecular pathogenesis.

»Gott segne Kupfer« Goethes Kunstbeschreibungen im Zeitalter der semitechnischen Reproduzierbarkeit

2017 ◽  
Vol 80 (3) ◽  
pp. 392-417
Author(s):  
Mattias Pirholt
Keyword(s):  
Crucial Role ◽  
Original Work ◽  
Continuous Process ◽  
Work Experiences ◽  
Autobiographical Accounts ◽  
Plaster Casts

Abstract This study investigates how the experience of reproductions – drawings, copperplate engravings, woodcuts, lithography, plaster casts, and so forth – influenced Johann Wolfgang von Goethe’s conception of art in general and his descriptions of art (e.g., ekphrases, reviews, and autobiographical accounts) in particular. Well acquainted with the technologies of reproduction of his time, Goethe, often in collaboration with Johann Heinrich Meyer, acknowledged the crucial role of reproductions for the understanding of the productive idea of the original work. Experiences of reproductions and comparisons between copies, drafts, and the original enabled Goethe to grasp the idea as an ever-transforming productive constant of the continuous process of becoming of the work.

scholarly journals Dynamics of Monolayer Growth in Vapor–Liquid–Solid GaAs Nanowires Based on Surface Energy Minimization

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1681
Author(s):  
Hadi Hijazi ◽  
Vladimir G. Dubrovskii
Keyword(s):  
Surface Energy ◽  
Continuous Process ◽  
Vapor Liquid Solid ◽  
Gaas Nanowires ◽  
Monolayer Growth ◽  
Surface Energetics ◽  
Monolayer Expansion ◽  
Vapor Liquid Solid Growth ◽  
Vapor Liquid

The vapor–liquid–solid growth of III-V nanowires proceeds via the mononuclear regime, where only one island nucleates in each nanowire monolayer. The expansion of the monolayer is governed by the surface energetics depending on the monolayer size. Here, we study theoretically the role of surface energy in determining the monolayer morphology at a given coverage. The optimal monolayer configuration is obtained by minimizing the surface energy at different coverages for a set of energetic constants relevant for GaAs nanowires. In contrast to what has been assumed so far in the growth modeling of III-V nanowires, we find that the monolayer expansion may not be a continuous process. Rather, some portions of the already formed monolayer may dissolve on one of its sides, with simultaneous growth proceeding on the other side. These results are important for fundamental understanding of vapor–liquid–solid growth at the atomic level and have potential impacts on the statistics within the nanowire ensembles, crystal phase, and doping properties of III-V nanowires.

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