scholarly journals The Biological Function and Roles in Phytohormone Signaling of the F-Box Protein in Plants

Agronomy ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2360
Author(s):  
Keheng Xu ◽  
Nan Wu ◽  
Wenbo Yao ◽  
Xiaowei Li ◽  
Yonggang Zhou ◽  
...  
Keyword(s):  
Ubiquitin Ligases ◽  
Degradation Pathway ◽  
E3 Ligases ◽  
Substrate Protein ◽  
Physiological Processes ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein ◽  
External Stimuli ◽  
Ligase Function

The ubiquitin–proteasome pathway (UPP) is an important protein degradation pathway that can participate in the regulation of the physiological process of organisms by specifically removing abnormal peptides and degrading cell regulators. UPP mainly involves three enzymes, among which the E3 ubiquitin ligase function is central to UPP. E3 ubiquitin ligases can recruit substrate protein for ubiquitination, and they have various forms. Among them, the Skp1–Cul1–F-box (SCF) complex is the most representative member of the cullin RING ubiquitin ligases type in RING-domain E3 ligases, being mainly composed of Cullin 1, Skp1, Rbx1, and F-box proteins. The F-box protein is the key component for SCF to perform specific functions. The F-box protein is one of the largest protein families in plants, and its family members are involved in the regulation of many key physiological processes, such as growth and development of plants and the response to external stimuli. Herein, we briefly review the structure, classification, function, and hormone signaling pathways of F-box proteins.

scholarly journals The importance of ubiquitin E3 ligases, SCF and APC/C, in human cancers

2015 ◽  
Vol 88 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Ovidiu Vasile Bochis ◽  
Bogdan Fetica ◽  
Catalin Vlad ◽  
Patriciu Achimas-Cadariu ◽  
Alexandru Irimie
Keyword(s):  
Cell Cycle ◽  
Anaphase Promoting Complex ◽  
E3 Ligases ◽  
Cyclin Dependent Kinases ◽  
Ubiquitin Proteasome Pathway ◽  
Complex Process ◽  
Target Therapies ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein

     A normal evolution of the cell-cycle phases consists of multiple consecutive events, which makes it a highly complex process. Its preservation is regulated by Cyclin-Cdks (cyclin-dependent kinases) interactions and protein degradation, which is often controlled by the ubiquitin-mediated proteolysis.The goal of this review is to emphasize the most important features of the regulation of the cell-cycle involved in cancerogenesis, by presenting the involvement of E3 ubiquitin ligases SCF (Skp1-Cul1-F-box protein) and APC/C (Anaphase-promoting complex/cyclosome) in human malignancies. Also, we discuss the importance of the ubiquitin proteasome pathway blockade in cancer treatment. We know that a better understanding of the regulatory biology of the cell cycle can lead to the development of new target therapies for cancer.

scholarly journals Regulation of p63 Protein Stability via Ubiquitin-Proteasome Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Chenghua Li ◽  
Zhi-Xiong Xiao
Keyword(s):  
Protein Stability ◽  
Biological Activities ◽  
Degradation Pathway ◽  
Protein Isoforms ◽  
E3 Ligases ◽  
Protein Levels ◽  
Extracellular Signaling ◽  
Multiple Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The p53-related p63 gene encodes multiple protein isoforms, which are involved in a variety of biological activities. p63 protein stability is mainly regulated by the ubiquitin-dependent proteasomal degradation pathway. Several ubiquitin E3 ligases have been identified and some protein kinases as well as other kinds of proteins are involved in regulation of p63 protein stability. These regulators are responsive to diverse extracellular signaling, resulting in changes of the p63 protein levels and impacting different biological processes.

scholarly journals ATF4 Degradation Relies on a Phosphorylation-Dependent Interaction with the SCFβTrCPUbiquitin Ligase

2001 ◽  
Vol 21 (6) ◽  
pp. 2192-2202 ◽  
Author(s):  
Irina Lassot ◽  
Emmanuel Ségéral ◽  
Clarisse Berlioz-Torrent ◽  
Herve Durand ◽  
Lionel Groussin ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Bzip Transcription Factor ◽  
Serine Residue ◽  
Receptor Component ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein ◽  
Bzip Family ◽  
Dependent Interaction

ABSTRACT The ubiquitin-proteasome pathway regulates gene expression through protein degradation. Here we show that the F-box protein βTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IκBα and β-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. Association between the two proteins depends on ATF4 phosphorylation and on ATF4 serine residue 219 present in the context of DSGXXXS, which is similar but not identical to the motif found in other substrates of βTrCP. ATF4 ubiquitination in HeLa cells is enhanced in the presence of βTrCP. The F-box-deleted βTrCP protein behaves as a negative transdominant mutant that inhibits ATF4 ubiquitination and degradation and, subsequently, enhances its activity in cyclic AMP-mediated transcription. ATF4 represents a novel substrate for the SCFβTrCP complex, which is the first mammalian E3 ubiquitin ligase identified so far for the control of the degradation of a bZIP transcription factor.

scholarly journals The Impact of Paeoniflorin onα-Synuclein Degradation Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-8
Author(s):  
Zenglin Cai ◽  
Xinzhi Zhang ◽  
Yongjin Zhang ◽  
Xiuming Li ◽  
Jing Xu ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Fluorescence Intensity ◽  
Cell Damage ◽  
Degradation Pathway ◽  
Ubiquitin Proteasome Pathway ◽  
Pathway Expression ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
The Impact

Paeoniflorin (PF) is the major active ingredient in the traditional Chinese medicine Radix. It plays a neuroprotective role by regulating autophagy and the ubiquitin-proteasome degradation pathway. In this study, we found PF significantly reduced cell damage caused by MPP+, returning cells to normal state. Cell viability significantly improved after 24 h exposure to RAPA and PF in the MPP+ group (allP<0.01). CAT and SOD activities were significantly decreased after PF and RAPA treatment, compared with MPP+ (P<0.001). In addition, MPP+ activated both LC3-II and E1; RAPA increased LC3-II but inhibited E1. PF significantly upregulated both LC3-II (autophagy) and E1 (ubiquitin-proteasome pathway) expression (P<0.001), promoted degradation ofα-synuclein, and reduced cell damage. We show MPP+ enhanced immunofluorescence signal of intracellularα-synuclein and LC3. Fluorescence intensity ofα-synuclein decreased after PF treatment. In conclusion, these data show PF reversed the decline of proteasome activity caused by MPP+ and significantly upregulated both autophagy and ubiquitin-proteasome pathways, promoted the degradation ofα-synuclein, and reduced cell damage. These findings suggest PF is a potential therapeutic medicine for neurodegenerative diseases.

scholarly journals The degradation of Rap1GAP via E6AP-mediated ubiquitin-proteasome pathway is associated with HPV16/18-infection in cervical cancer cells

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yinghui Wang ◽  
Yihang Xie ◽  
Boxuan Sun ◽  
Yuwei Guo ◽  
Ling Song ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Suppressor Gene ◽  
Hpv Infection ◽  
Degradation Pathway ◽  
Human Papillomaviruses ◽  
Siha Cells ◽  
Cervical Cancer Cells ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract Background Cervical cancers are closely associated with persistent high-risk human papillomaviruses (HR HPV) infection. The main mechanism involves the targeting of tumor suppressors, such as p53 and pRB, for degradation by HR HPV-encoded oncoproteins, thereby leading to tumorigenesis. Rap1GAP, a tumor suppressor gene, is down-regulated in many cancers. Previous studies have revealed that down-regulation of Rap1GAP is correlated with HPV16/18 infection in cervical cancer. However, the molecular mechanism remains unclear. In this study, we aimed to address the degradation pathway of Rap1GAP in HPV-positive cervical cancer cells. Methods HPV-positive (HeLa and SiHa) and negative (C33A) cervical cancer cells were used to analyze the pathways of Rap1GAP degradation. MG132 (carbobenzoxy-leucyl-leucyl-leucine) was used to inhibit protein degradation by proteasome. Co-immunoprecipitation (co-IP) was used to detect the interaction between Rap1GAP and E6AP. siRNA for E6AP was used to silence the expression of E6AP. Rapamycin was used to induce cell autophagy. Western blotting was used to check the levels of proteins. Results Following treatment with MG132, the levels of Rap1GAP were increased in the HR HPV-positive HeLa and SiHa cells, but not in the HPV-negative C33A cells. Co-immunoprecipitation assay revealed ubiquitinated Rap1GAP protein in HeLa and SiHa cells, but not in C33A cells. E6-associated protein (E6AP) mediated the ubiquitination of Rap1GAP by binding to it in HeLa and SiHa cells, but not in C33A cells. However, the levels of Rap1GAP were decreased in HeLa and SiHa cells after knocking down E6AP by siRNA. Silencing of E6AP did not affect the levels of Rap1GAP in C33A cells. Autophagy marker p62 was decreased and LC3 II/LC3 I was increased after knocking down E6AP in HeLa cells, but not in C33A cells. The levels of Rap1GAP were decreased after treating the cells with rapamycin to induce cell autophagy in HeLa and C33A cells. Conclusion Rap1GAP may be degraded by autophagy in cervical cancer cells, but HPV infection can switch the degradation pathway from autophagy to E6AP-mediated ubiquitin-proteasome degradation. E6AP may be a key component of the switch.

scholarly journals Discovery of Therapeutic Deubiquitylase Effector Molecules

2014 ◽  
Vol 19 (7) ◽  
pp. 989-999 ◽  
Author(s):  
B. Nicholson ◽  
Suresh Kumar ◽  
S. Agarwal ◽  
M. J. Eddins ◽  
J. G. Marblestone ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Proteasome Inhibitors ◽  
Therapeutic Targets ◽  
Cysteine Proteases ◽  
Preclinical Development ◽  
E3 Ligases ◽  
The Past ◽  
Novel Drugs ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The approval of proteasome inhibitors bortezomib and carfilzomib and the E3 ligase antagonist thalidomide and its analogs, lenalidomide and pomalidomide, validates the ubiquitin–proteasome pathway as a source of novel drugs for treating cancer and, potentially, a variety of devastating illnesses, including inflammation, cardiovascular disease, and neurodegenerative disease. All elements of this critical regulatory pathway—the proteasome itself, E3 ligases (which conjugate ubiquitin to target proteins), and deubiquitylating enzymes (which deconjugate ubiquitin, reversing ligase action)—are potential therapeutic targets, and all have been worked on extensively during the past decade. No deubiquitylase inhibitors or activators have yet progressed to clinical trial, however, despite compelling target validation and several years of high-throughput screening and preclinical development of hits by numerous pharmaceutical companies, biotechnology organizations, and academic groups. The appropriateness of deubiquitylases as therapeutic targets in many disease areas is reviewed, followed by evidence that selective inhibitors of these cysteine proteases can be discovered. Because the lack of progress in drug-discovery efforts with deubiquitylases suggests a need for improved discovery methodologies, currently available platforms and strategies are analyzed, and improved or completely novel, unrelated approaches are considered in terms of their likelihood of producing clinically viable effectors of deubiquitylases.

scholarly journals Role of Sec61p in the ER-associated degradation of short-lived transmembrane proteins

2008 ◽  
Vol 181 (7) ◽  
pp. 1095-1105 ◽  
Author(s):  
Daniel C. Scott ◽  
Randy Schekman
Keyword(s):  
Degradation Process ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Specific Protein ◽  
Cysteine Residue ◽  
Misfolded Proteins ◽  
Er Quality Control ◽  
Substrate Protein ◽  
Ubiquitin Proteasome ◽  
Protein Components

Misfolded proteins in the endoplasmic reticulum (ER) are identified and degraded by the ER-associated degradation pathway (ERAD), a component of ER quality control. In ERAD, misfolded proteins are removed from the ER by retrotranslocation into the cytosol where they are degraded by the ubiquitin–proteasome system. The identity of the specific protein components responsible for retrotranslocation remains controversial, with the potential candidates being Sec61p, Der1p, and Doa10. We show that the cytoplasmic N-terminal domain of a short-lived transmembrane ERAD substrate is exposed to the lumen of the ER during the degradation process. The addition of N-linked glycan to the N terminus of the substrate is prevented by mutation of a specific cysteine residue of Sec61p, as well as a specific cysteine residue of the substrate protein. We show that the substrate protein forms a disulfide-linked complex to Sec61p, suggesting that at least part of the retrotranslocation process involves Sec61p.

scholarly journals The Effect of Dysfunctional Ubiquitin Enzymes in the Pathogenesis of Most Common Diseases

2020 ◽  
Vol 21 (17) ◽  
pp. 6335 ◽  
Author(s):  
Gizem Celebi ◽  
Hale Kesim ◽  
Ebru Ozer ◽  
Ozlem Kutlu
Keyword(s):  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzymes ◽  
E3 Ligases ◽  
Substrate Protein ◽  
Common Diseases ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugating Enzymes ◽  
Substrate Proteins

Ubiquitination is a multi-step enzymatic process that involves the marking of a substrate protein by bonding a ubiquitin and protein for proteolytic degradation mainly via the ubiquitin–proteasome system (UPS). The process is regulated by three main types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). Under physiological conditions, ubiquitination is highly reversible reaction, and deubiquitinases or deubiquitinating enzymes (DUBs) can reverse the effect of E3 ligases by the removal of ubiquitin from substrate proteins, thus maintaining the protein quality control and homeostasis in the cell. The dysfunction or dysregulation of these multi-step reactions is closely related to pathogenic conditions; therefore, understanding the role of ubiquitination in diseases is highly valuable for therapeutic approaches. In this review, we first provide an overview of the molecular mechanism of ubiquitination and UPS; then, we attempt to summarize the most common diseases affecting the dysfunction or dysregulation of these mechanisms.

scholarly journals BAG2-Mediated Inhibition of CHIP Expression and Overexpression of MDM2 Contribute to the Initiation of Endometriosis by Modulating Estrogen Receptor Status

2021 ◽  
Vol 8 ◽  
Author(s):  
Li-Juan Chen ◽  
Bin Hu ◽  
Zhi-Qiang Han ◽  
Jian-Hua Zhu ◽  
Xu Fan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Molecular Mechanisms ◽  
Estrogenic Activity ◽  
Estrogen Receptor Status ◽  
Therapeutic Effects ◽  
Childbearing Age ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Endometriosis is an estrogen-dependent gynecological disease primarily affecting women of childbearing age, which gives rise to pelvic pain calling for multiple operations, and sometimes leading to infertility. However, the etiology of endometriosis remains poorly understood. In this study we investigated the roles of two Ubiquitin E3 Ligases, namely hsc70-interacting protein (CHIP) and mouse double minute 2 (MDM2), in the abnormal estrogenic activity in endometriosis. We first collected endometrial tissues from 91 cases of endometriosis and 78 cases of uterine myomas. Next, we established a murine endometriosis model by ectopic endometrial tissue implantation. In other studies, we isolated human endometrial stromal cells (HESCs) were isolated from the endometrial tissues, and performed HA- or FLAG-immunoprecipitation assays and immunoblotting with an anti-ubiquitin antibody to test the interactions among BAG2, CHIP, MDM2, estrogen receptor α (ERα), and ERβ. The expression of ERα was downregulated while that of ERβ, BAG2, and MDM2 was upregulated in human endometriosis and in the mouse model. CHIP degraded ERβ instead of ERα via the ubiquitin-proteasome pathway, while BAG2 impaired the CHIP-mediated degradation of ERβ in cultured HESCs derived from human endometriosis. The degradation of ERα by MDM2 in cultured endometriosis-HESCs also occurred through the ubiquitin-proteasome pathway. Knockdown of both BAG2 and MDM2 alleviated the development of endometriosis in mice. Our findings suggest that the interference of BAG2 and MDM2 may have therapeutic effects in endometriosis. Understanding better the molecular mechanisms underlying the regulation of the abnormal estrogenic activity in endometriosis is crucial for the advancement of targeted therapeutic strategies.

The ubiquitin–proteasome pathway in viral infectionsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Guang Gao ◽  
Honglin Luo
Keyword(s):  
Critical Role ◽  
Proteasome Inhibition ◽  
Degradation Pathway ◽  
Enteroviral Infection ◽  
Ubiquitin Proteasome Pathway ◽  
Potential Therapeutic Application ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function

The cellular biological function of the ubiquitin–proteasome pathway as a major intracellular protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated over the last decade. The critical role of the ubiquitin–proteasome pathway in viral pathogenesis has become increasingly apparent. Many viruses have been reported to evolve different strategies to utilize the ubiquitin–proteasome pathway for their own benefits. Here, we review the general background and function of the ubiquitin–proteasome pathway, summarize our current understanding of how viruses use this pathway to target cellular proteins, and finally, discuss the roles of this pathway in enteroviral infection, and the potential therapeutic application of proteasome inhibition in myocarditis.

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