scholarly journals Selective Autophagy by Close Encounters of the Ubiquitin Kind

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2349 ◽  
Author(s):  
Anna Vainshtein ◽  
Paolo Grumati
Keyword(s):  
Protein Aggregates ◽  
Degradation Process ◽  
Eukaryotic Cells ◽  
Post Translational Modifications ◽  
Selective Autophagy ◽  
Close Encounters ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Cellular Turnover

Autophagy, a bulk degradation process within eukaryotic cells, is responsible for cellular turnover and nutrient liberation during starvation. Increasing evidence indicate that this process can be extremely discerning. Selective autophagy segregates and eliminates protein aggregates, damaged organelles, and invading organisms. The specificity of this process is largely mediated by post-translational modifications (PTMs), which are recognized by autophagy receptors. These receptors grant autophagy surgical precision in cargo selection, where only tagged substrates are engulfed within autophagosomes and delivered to the lysosome for proteolytic breakdown. A growing number of selective autophagy receptors have emerged including p62, NBR1, OPTN, NDP52, TAX1BP1, TOLLIP, and more continue to be uncovered. The most well-documented PTM is ubiquitination and selective autophagy receptors are equipped with a ubiquitin binding domain and an LC3 interacting region which allows them to physically bridge cargo to autophagosomes. Here, we review the role of ubiquitin and ubiquitin-like post-translational modifications in various types of selective autophagy.

scholarly journals The Role of Beclin 1-Dependent Autophagy in Cancer

Biology ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 4 ◽  
Author(s):  
Silvia Vega-Rubín-de-Celis
Keyword(s):  
Dna Damage ◽  
Tumor Suppression ◽  
Protein Aggregates ◽  
Degradation Process ◽  
Beclin 1 ◽  
Cancer Type ◽  
Intracellular Degradation

Autophagy (self-eating) is an intracellular degradation process used by cells to keep a “clean house”; as it degrades abnormal or damaged proteins and organelles, it helps to fight infections and also provides energy in times of fasting or exercising. Autophagy also plays a role in cancer, although its precise function in each cancer type is still obscure, and whether autophagy plays a protecting (through the clearing of damaged organelles and protein aggregates and preventing DNA damage) or a promoting (by fueling the already stablished tumor) role in cancer remains to be fully characterized. Beclin 1, the mammalian ortholog of yeast Atg6/Vps30, is an essential autophagy protein and has been shown to play a role in tumor suppression. Here, an update of the tumorigenesis regulation by Beclin 1-dependent autophagy is provided.

scholarly journals Role of the ubiquitin-binding domain of Polη in Rad18-independent translesion DNA synthesis in human cell extracts

2010 ◽  
Vol 38 (19) ◽  
pp. 6456-6465 ◽  
Author(s):  
Valérie Schmutz ◽  
Régine Janel-Bintz ◽  
Jérôme Wagner ◽  
Denis Biard ◽  
Naoko Shiomi ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Human Cell ◽  
Binding Domain ◽  
Translesion Dna Synthesis ◽  
Cell Extracts ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Translesion Dna

scholarly journals The role of spartin and its novel ubiquitin binding region in DALIS occurrence

2014 ◽  
Vol 25 (8) ◽  
pp. 1355-1365 ◽  
Author(s):  
Amelia B. Karlsson ◽  
Jacqueline Washington ◽  
Valentina Dimitrova ◽  
Christopher Hooper ◽  
Alexander Shekhtman ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Resonance Spectroscopy ◽  
Spastic Paraplegia ◽  
Binding Region ◽  
Hairpin Rna ◽  
Multifunctional Protein ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Key Residues

Troyer syndrome is an autosomal recessive hereditary spastic paraplegia (HSP) caused by frameshift mutations in the SPG20 gene that results in a lack of expression of the truncated protein. Spartin is a multifunctional protein, yet only two conserved domains—a microtubule-interacting and trafficking domain and a plant-related senescence domain involved in cytokinesis and mitochondrial physiology, respectively—have been defined. We have shown that overexpressed spartin binds to the Ile44 hydrophobic pocket of ubiquitin, suggesting spartin might contain a ubiquitin-binding domain. In the present study, we demonstrate that spartin contributes to the formation of dendritic aggresome-like induced structures (DALIS) through a unique ubiquitin-binding region (UBR). Using short hairpin RNA, we knocked down spartin in RAW264.7 cells and found that DALIS frequency decreased; conversely, overexpression of spartin increased the percentage of cells containing DALIS. Using nuclear magnetic resonance spectroscopy, we characterized spartin's UBR and defined the UBR's amino acids that are key for ubiquitin binding. We also found that spartin, via the UBR, binds Lys-63–linked ubiquitin chains but does not bind Lys-48–linked ubiquitin chains. Finally, we demonstrate that spartin's role in DALIS formation depends on key residues within its UBR.

scholarly journals Are stress granules the RNA analogs of misfolded protein aggregates?

RNA ◽  
2021 ◽  
pp. rna.079000.121
Author(s):  
Nina Ripin ◽  
Roy Parker
Keyword(s):  
Protein Aggregates ◽  
Eukaryotic Cells ◽  
Misfolded Protein ◽  
Granule Formation ◽  
Unfolded Protein ◽  
Rna Chaperones ◽  
Rnp Granules ◽  
Disease Understanding ◽  
Insight Into

RNP granules are ubiquitous features of eukaryotic cells. Several observations argue that the formation of at least some RNP granules can be considered analogous to the formation of unfolded protein aggregates. First, unfolded protein aggregates form from the exposure of promiscuous protein interaction surfaces, while some mRNP granules form, at least in part, by promiscuous intermolecular RNA-RNA interactions due to exposed RNA surfaces when mRNAs are not engaged with ribosomes. Second, analogous to the role of protein chaperones in preventing misfolded protein aggregation, cells contain abundant “RNA chaperones” to limit inappropriate RNA-RNA interactions and prevent mRNP granule formation. Third, analogous to the role of protein aggregates in diseases, situations where RNA aggregation exceeds the capacity of RNA chaperones to disaggregate RNAs may contribute to human disease. Understanding that RNP granules can be considered as promiscuous, reversible RNA aggregation events allows insight into their composition and how cells have evolved functions for RNP granules.

scholarly journals Ubiquitin, Autophagy and Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2022 ◽  
Author(s):  
Yoshihisa Watanabe ◽  
Katsutoshi Taguchi ◽  
Masaki Tanaka
Keyword(s):  
Neurodegenerative Diseases ◽  
Ubiquitin Proteasome System ◽  
Binding Domain ◽  
Therapeutic Application ◽  
Selective Autophagy ◽  
Ubiquitin Binding ◽  
Selective Incorporation ◽  
Ubiquitin Binding Domain ◽  
Ubiquitin Proteasome ◽  
Autophagy Activity

Ubiquitin signals play various roles in proteolytic and non-proteolytic functions. Ubiquitin signals are recognized as targets of the ubiquitin–proteasome system and the autophagy–lysosome pathway. In autophagy, ubiquitin signals are required for selective incorporation of cargoes, such as proteins, organelles, and microbial invaders, into autophagosomes. Autophagy receptors possessing an LC3-binding domain and a ubiquitin binding domain are involved in this process. Autophagy activity can decline as a result of genetic variation, aging, or lifestyle, resulting in the onset of various neurodegenerative diseases. This review summarizes the selective autophagy of neurodegenerative disease-associated protein aggregates via autophagy receptors and discusses its therapeutic application for neurodegenerative diseases.

scholarly journals Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy

2021 ◽  
Vol 220 (6) ◽  
Author(s):  
Thaddaeus Mutugi Nthiga ◽  
Birendra Kumar Shrestha ◽  
Jack-Ansgar Bruun ◽  
Kenneth Bowitz Larsen ◽  
Trond Lamark ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Golgi Complex ◽  
Eukaryotic Cells ◽  
Golgi Membrane ◽  
Selective Autophagy ◽  
Physiological Demands ◽  
Size And Morphology ◽  
In Cells

The Golgi complex is essential for the processing, sorting, and trafficking of newly synthesized proteins and lipids. Golgi turnover is regulated to meet different cellular physiological demands. The role of autophagy in the turnover of Golgi, however, has not been clarified. Here we show that CALCOCO1 binds the Golgi-resident palmitoyltransferase ZDHHC17 to facilitate Golgi degradation by autophagy during starvation. Depletion of CALCOCO1 in cells causes expansion of the Golgi and accumulation of its structural and membrane proteins. ZDHHC17 itself is degraded by autophagy together with other Golgi membrane proteins such as TMEM165. Taken together, our data suggest a model in which CALCOCO1 mediates selective Golgiphagy to control Golgi size and morphology in eukaryotic cells via its interaction with ZDHHC17.

scholarly journals Oligomerization of Selective Autophagy Receptors for the Targeting and Degradation of Protein Aggregates

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1989
Author(s):  
Wenjun Chen ◽  
Tianyun Shen ◽  
Lijun Wang ◽  
Kefeng Lu
Keyword(s):  
Phase Separation ◽  
Binding Protein ◽  
Protein Aggregates ◽  
Selective Autophagy ◽  
Binding Domains ◽  
Selective Targeting ◽  
Ubiquitin Binding

The selective targeting and disposal of solid protein aggregates are essential for cells to maintain protein homoeostasis. Autophagy receptors including p62, NBR1, Cue5/TOLLIP (CUET), and Tax1-binding protein 1 (TAX1BP1) proteins function in selective autophagy by targeting ubiquitinated aggregates through ubiquitin-binding domains. Here, we summarize previous beliefs and recent findings on selective receptors in aggregate autophagy. Since there are many reviews on selective autophagy receptors, we focus on their oligomerization, which enables receptors to function as pathway determinants and promotes phase separation.

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 Discovery of Novel Regulators of Autophagy in Animals

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 744-744
Author(s):  
Eric Baehrecke
Keyword(s):  
Cell Size ◽  
Movement Disorders ◽  
Essential Gene ◽  
Human Movement ◽  
Protein Aggregates ◽  
The Novel ◽  
Degenerative Disorders ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Encoding Genes

Abstract The clearance of organelles by autophagy is important for cell health, and defects in this process have been associated with age-associated degenerative disorders. Ubiquitination of proteins enables their recognition by cargo receptors that facilitate the delivery of both protein aggregates and organelles to forming autophagosomes for degradation. We have investigated developmentally programmed autophagy to identify novel regulators of organelle clearance. We identified an Atg7-independent autophagy program that is required for cell size reduction and clearance of mitochondria. We have used this system to screen for new factors regulate ubiquitin-dependent autophagy and clearance of organelles. We screened a collection of putative ubiquitin binding domain encoding genes, and identified the novel gene Vps13D. Vps13D is an essential gene that is necessary for autophagy, mitochondrial size, mitochondrial clearance, and is associated with human movement disorders. We have used genetics and biochemistry to identify factors that link Vps13D, mitochondrial biology and autophagy.

scholarly journals Autophagy Receptor Protein Tax1-Binding Protein 1/TRAF6-Binding Protein Is a Cellular Substrate of Enteroviral Proteinase

2021 ◽  
Vol 12 ◽  
Author(s):  
Yasir Mohamud ◽  
Yuan Chao Xue ◽  
Huitao Liu ◽  
Chen Seng Ng ◽  
Amirhossein Bahreyni ◽  
...  
Keyword(s):  
Binding Protein ◽  
Receptor Protein ◽  
Late Infection ◽  
Culture Studies ◽  
Selective Autophagy ◽  
Protein Levels ◽  
Cvb3 Infection ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Autophagy Pathway

Enteroviruses (EVs) usurp the host autophagy pathway for pro-viral functions; however, the consequence of EV-induced diversion of autophagy on organelle quality control is poorly defined. Using coxsackievirus B3 (CVB3) as a model EV, we explored the interplay between EV infection and selective autophagy receptors, i.e., Tax1-binding protein 1/TRAF6-binding protein (T6BP), optineurin (OPTN), and nuclear dot 10 protein 52 (NDP52), known to be involved in regulating the clearance of damaged mitochondria, a process termed as mitophagy. Following CVB3 infection, we showed significant perturbations of the mitochondrial network coincident with degradation of the autophagy receptor protein T6BP, similar phenomenon to what we previously observed on NDP52. Notably, protein levels of OPTN are not altered during early infection and slightly reduced upon late infection. Cell culture studies revealed that T6BP degradation occurs independent of the function of host caspases and viral proteinase 3C, but requires the proteolytic activity of viral proteinase 2A. Further investigation identified the cleavage site on T6BP after the amino acid 621 that separates the C-terminal ubiquitin-binding domain from the other functional domains at the N-terminus. Genetic silencing of T6BP and OPTN results in the attenuation of CVB3 replication, suggesting a pro-viral activity for these two proteins. Finally, functional assessment of cleaved fragments from NDP52 and T6BP revealed abnormal binding affinity and impaired capacity to be recruited to depolarized mitochondria. Collectively, these results suggest that CVB3 targets autophagy receptors to impair selective autophagy.

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