scholarly journals Ubiquitin-mediated regulation of autophagy

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Ruey-Hwa Chen ◽  
Yu-Hsuan Chen ◽  
Tzu-Yu Huang
Keyword(s):  
Reciprocal Cross ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Degradation Pathways ◽  
Cell Homeostasis ◽  
Polyubiquitin Chains ◽  
Selective Autophagy ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome

Abstract Autophagy is a major degradation pathway that utilizes lysosome hydrolases to degrade cellular constituents and is often induced under cellular stress conditions to restore cell homeostasis. Another prime degradation pathway in the cells is ubiquitin-proteasome system (UPS), in which proteins tagged by certain types of polyubiquitin chains are selectively recognized and removed by proteasome. Although the two degradation pathways are operated independently with different sets of players, recent studies have revealed reciprocal cross talks between UPS and autophagy at multiple layers. In this review, we summarize the roles of protein ubiquitination and deubiquitination in controlling the initiation, execution, and termination of bulk autophagy as well as the role of ubiquitination in signaling certain types of selective autophagy. We also highlight how dysregulation of ubiquitin-mediated autophagy pathways is associated with a number of human diseases and the potential of targeting these pathways for disease intervention.

scholarly journals The Role of Autophagy and Autophagy Receptor NDP52 in Microbial Infections

2020 ◽  
Vol 21 (6) ◽  
pp. 2008 ◽  
Author(s):  
Shuangqi Fan ◽  
Keke Wu ◽  
Mengpo Zhao ◽  
Erpeng Zhu ◽  
Shengming Ma ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Protective Mechanism ◽  
Pathogenic Microorganism ◽  
Microbial Infection ◽  
Selective Autophagy ◽  
Microbial Infections ◽  
Ubiquitin Proteasome ◽  
Cellular Components

Autophagy is a general protective mechanism for maintaining homeostasis in eukaryotic cells, regulating cellular metabolism, and promoting cell survival by degrading and recycling cellular components under stress conditions. The degradation pathway that is mediated by autophagy receptors is called selective autophagy, also named as xenophagy. Autophagy receptor NDP52 acts as a ‘bridge’ between autophagy and the ubiquitin-proteasome system, and it also plays an important role in the process of selective autophagy. Pathogenic microbial infections cause various diseases in both humans and animals, posing a great threat to public health. Increasing evidence has revealed that autophagy and autophagy receptors are involved in the life cycle of pathogenic microbial infections. The interaction between autophagy receptor and pathogenic microorganism not only affects the replication of these microorganisms in the host cell, but it also affects the host’s immune system. This review aims to discuss the effects of autophagy on pathogenic microbial infection and replication, and summarizes the mechanisms by which autophagy receptors interact with microorganisms. While considering the role of autophagy receptors in microbial infection, NDP52 might be a potential target for developing effective therapies to treat pathogenic microbial infections.

scholarly journals The Role of ATG16 in Autophagy and The Ubiquitin Proteasome System

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 2 ◽  
Author(s):  
Qiuhong Xiong ◽  
Wenjing Li ◽  
Ping Li ◽  
Min Yang ◽  
Changxin Wu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathways ◽  
Autophagosome Formation ◽  
Cell Homeostasis ◽  
Independent Functions ◽  
Ubiquitin Proteasome

Autophagy and the ubiquitin proteasome system (UPS) are the two major cellular degradation pathways, which are critical for the maintenance of cell homeostasis. The two pathways differ in their mechanisms and clients. The evolutionary conserved ATG16 plays a key role in autophagy and appears to link autophagy with the UPS. Here, we review the role of ATG16 in different species. We summarize the current knowledge of its functions in autophagosome membrane expansion and autophagosome formation, in Crohn’s disease, and in bacterial sequestration. In addition, we provide information on its autophagy-independent functions and its role in the crosstalk between autophagy and the UPS.

scholarly journals The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Mónika Lippai ◽  
Péter Lőw
Keyword(s):  
Ubiquitin Proteasome System ◽  
Degradation Pathways ◽  
Intracellular Pathogens ◽  
Protein Conjugation ◽  
Cytosolic Proteins ◽  
Ubiquitin Binding ◽  
Ubiquitin Proteasome ◽  
Point Of Intersection

The ubiquitin-proteasome system and autophagy were long viewed as independent, parallel degradation systems with no point of intersection. By now we know that these degradation pathways share certain substrates and regulatory molecules and show coordinated and compensatory function. Two ubiquitin-like protein conjugation pathways were discovered that are required for autophagosome biogenesis: the Atg12-Atg5-Atg16 and Atg8 systems. Autophagy has been considered to be essentially a nonselective process, but it turned out to be at least partially selective. Selective substrates of autophagy include damaged mitochondria, intracellular pathogens, and even a subset of cytosolic proteins with the help of ubiquitin-binding autophagic adaptors, such as p62/SQSTM1, NBR1, NDP52, and Optineurin. These proteins selectively recognize autophagic cargo and mediate its engulfment into autophagosomes by binding to the small ubiquitin-like modifiers that belong to the Atg8/LC3 family.

scholarly journals Canonical and non-canonical autophagy pathways in microglia

2020 ◽  
Author(s):  
Julia Jülg ◽  
Laura Strohm ◽  
Christian Behrends
Keyword(s):  
Neurodegenerative Disorders ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Brain Health ◽  
The Past ◽  
Long Time ◽  
Ubiquitin Proteasome ◽  
Autophagy Activity

Besides the ubiquitin-proteasome-system, autophagy is a major degradation pathway within cells. It delivers invading pathogens, damaged organelles, aggregated proteins and other macromolecules from the cytosol to the lysosome for bulk degradation. This so-called canonical autophagy activity contributes to the maintenance of organelle, protein and metabolite homeostasis as well as innate immunity. Over the past years, numerous studies rapidly deepened our knowledge on the autophagy machinery and its regulation; driven by the fact that impairment of autophagy is associated with several human pathologies including cancer, immune diseases and neurodegenerative disorders. Unexpectedly, components of the autophagic machinery were also found to participate in various processes that did not involve lysosomal delivery of cytosolic constituents. These functions are hereafter defined as non-canonical autophagy. Regarding neurodegenerative diseases, most research was performed in neurons, while for a long-time microglia received considerably less attention. Concomitant with the notion that microglia greatly contribute to brain health, the understanding of the role of autophagy in microglia expanded. To facilitate an overview of the current knowledge, we present herein the fundamentals as well as the recent advances of canonical and non-canonical autophagy functions in microglia.

scholarly journals The Ubiquitin-Proteasome System Plays an Important Role during Various Stages of the Coronavirus Infection Cycle

2010 ◽  
Vol 84 (15) ◽  
pp. 7869-7879 ◽  
Author(s):  
Matthijs Raaben ◽  
Clara C. Posthuma ◽  
Monique H. Verheije ◽  
Eddie G. te Lintelo ◽  
Marjolein Kikkert ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ubiquitin Proteasome System ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Infection Cycle ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome ◽  
The Impact ◽  
In Cells

ABSTRACT The ubiquitin-proteasome system (UPS) is a key player in regulating the intracellular sorting and degradation of proteins. In this study we investigated the role of the UPS in different steps of the coronavirus (CoV) infection cycle. Inhibition of the proteasome by different chemical compounds (i.e., MG132, epoxomicin, and Velcade) appeared to not only impair entry but also RNA synthesis and subsequent protein expression of different CoVs (i.e., mouse hepatitis virus [MHV], feline infectious peritonitis virus, and severe acute respiratory syndrome CoV). MHV assembly and release were, however, not appreciably affected by these compounds. The inhibitory effect on CoV protein expression did not appear to result from a general inhibition of translation due to induction of a cellular stress response by the inhibitors. Stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) generally results in impaired initiation of protein synthesis, but the sensitivity of MHV infection to proteasome inhibitors was unchanged in cells lacking a phosphorylatable eIF2α. MHV infection was affected not only by inhibition of the proteasome but also by interfering with protein ubiquitination. Viral protein expression was reduced in cells expressing a temperature-sensitive ubiquitin-activating enzyme E1 at the restrictive temperature, as well as in cells in which ubiquitin was depleted by using small interfering RNAs. Under these conditions, the susceptibility of the cells to virus infection was, however, not affected, excluding an important role of ubiquitination in virus entry. Our observations reveal an important role of the UPS in multiple steps of the CoV infection cycle and identify the UPS as a potential drug target to modulate the impact of CoV infection.

scholarly journals Hypoxia-induced alterations in the lung ubiquitin proteasome system during pulmonary hypertension pathogenesis

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401878826 ◽  
Author(s):  
Brandy E. Wade ◽  
Jingru Zhao ◽  
Jing Ma ◽  
C. Michael Hart ◽  
Roy L. Sutliff
Keyword(s):  
Mass Spectrometry ◽  
Pulmonary Hypertension ◽  
Ubiquitin Proteasome System ◽  
Global Changes ◽  
Clinical Disorder ◽  
Ubiquitinated Proteins ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome ◽  
Protein Alterations

Pulmonary hypertension (PH) is a clinical disorder characterized by sustained increases in pulmonary vascular resistance and pressure that can lead to right ventricular (RV) hypertrophy and ultimately RV failure and death. The molecular pathogenesis of PH remains incompletely defined, and existing treatments are associated with suboptimal outcomes and persistent morbidity and mortality. Reports have suggested a role for the ubiquitin proteasome system (UPS) in PH, but the extent of UPS-mediated non-proteolytic protein alterations during PH pathogenesis has not been previously defined. To further examine UPS alterations, the current study employed C57BL/6J mice exposed to normoxia or hypoxia for 3 weeks. Lung protein ubiquitination was evaluated by mass spectrometry to identify differentially ubiquitinated proteins relative to normoxic controls. Hypoxia stimulated differential ubiquitination of 198 peptides within 131 proteins ( p < 0.05). These proteins were screened to identify candidates within pathways involved in PH pathogenesis. Some 51.9% of the differentially ubiquitinated proteins were implicated in at least one known pathway contributing to PH pathogenesis, and 13% were involved in three or more PH pathways. Anxa2, App, Jak1, Lmna, Pdcd6ip, Prkch1, and Ywhah were identified as mediators in PH pathways that undergo differential ubiquitination during PH pathogenesis. To our knowledge, this is the first study to report global changes in protein ubiquitination in the lung during PH pathogenesis. These findings suggest signaling nodes that are dynamically regulated by the UPS during PH pathogenesis. Further exploration of these differentially ubiquitinated proteins and related pathways can provide new insights into the role of the UPS in PH pathogenesis.

scholarly journals Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1513
Author(s):  
Chee Wai Fhu ◽  
Azhar Ali
Keyword(s):  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Eukaryotic Cells ◽  
Lysosomal Degradation ◽  
Polyubiquitin Chains ◽  
Protein Levels ◽  
Cellular Processes ◽  
Ubiquitin Proteasome

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review.

scholarly journals Primary restriction of S-RNase cytotoxicity by a stepwise ubiquitination and degradation pathway in Petunia hybrida

2020 ◽  
Author(s):  
Hong Zhao ◽  
Yanzhai Song ◽  
Junhui Li ◽  
Yue Zhang ◽  
Huaqiu Huang ◽  
...  
Keyword(s):  
Marked Reduction ◽  
Petunia Hybrida ◽  
Ubiquitin Proteasome System ◽  
Pollen Tubes ◽  
Degradation Pathway ◽  
Rnase R ◽  
Polyubiquitin Chains ◽  
Solanaceous Species ◽  
Cross Pollination ◽  
Ubiquitin Proteasome

ABSTRACTIn self-incompatible Solanaceous species, the pistil S-RNase acts as cytotoxin to inhibit self-pollination but is polyubiquitinated by the pollen-specific non-self S-locus F-box (SLF) proteins and subsequently degraded by the ubiquitin-proteasome system (UPS), allowing cross-pollination. However, it remains unclear how S-RNase is restricted by the UPS. Here, we first show that Petunia hybrida (Ph) S3-RNase is largely ubiquitinated by K48-linked polyubiquitin chains at three regions, R I, II and III. R I is ubiquitinated in unpollinated, self- and cross-pollinated pistils, indicating its occurrence prior to PhS3-RNase uptake into pollen tubes, whereas R II and III are exclusively ubiquitinated in cross-pollinated pistils. Second, removal of R II ubiquitination resulted in significantly reduced seed sets from cross-pollination and that of R I and III in less extents, indicating their increased cytotoxicity. In consistent, the mutated R II of PhS3-RNase resulted in marked reduction of its degradation, whereas that of R I and III in less reductions. Taken together, our results demonstrate that PhS3-RNase R II functions as a major ubiquitination region for its destruction and R I and III as minor ones, revealing that its cytotoxicity is primarily restricted by a stepwise UPS mechanism for cross-pollination in P. hybrida.ONE SENTENCE SUMMARYBiochemical and transgenic analyses reveal that Petunia hybrida S3-RNase cytotoxicity is largely restricted by a stepwise ubiquitination and degradation pathway during cross-pollination.

The Ubiquitin-Proteasome System and Memory: Moving Beyond Protein Degradation

2018 ◽  
Vol 24 (6) ◽  
pp. 639-651 ◽  
Author(s):  
Timothy J. Jarome ◽  
Rishi K. Devulapalli
Keyword(s):  
Protein Degradation ◽  
Chromatin Remodeling ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Memory Formation ◽  
Consolidation Process ◽  
Future Studies ◽  
Cellular Models ◽  
Ubiquitin Proteasome

Cellular models of memory formation have focused on the need for protein synthesis. Recently, evidence has emerged that protein degradation mediated by the ubiquitin-proteasome system (UPS) is also important for this process. This has led to revised cellular models of memory formation that focus on a balance between protein degradation and synthesis. However, protein degradation is only one function of the UPS. Studies using single-celled organisms have shown that non-proteolytic ubiquitin-proteasome signaling is involved in histone modifications and DNA methylation, suggesting that ubiquitin and the proteasome can regulate chromatin remodeling independent of protein degradation. Despite this evidence, the idea that the UPS is more than a protein degradation pathway has not been examined in the context of memory formation. In this article, we summarize recent findings implicating protein degradation in memory formation and discuss various ways in which both ubiquitin signaling and the proteasome could act independently to regulate epigenetic-mediated transcriptional processes necessary for learning-dependent synaptic plasticity. We conclude by proposing comprehensive models of how non-proteolytic functions of the UPS could work in concert to control epigenetic regulation of the cellular memory consolidation process, which will serve as a framework for future studies examining the role of the UPS in memory formation.

Sign in / Sign up

Export Citation Format

Share Document