Topological and regulatory aspects of dolichyl phosphate mediated glycosylation of proteins

1982 ◽  
Vol 300 (1099) ◽  
pp. 129-144 ◽  
Keyword(s):  
Secretory Pathway ◽  
Membrane System ◽  
Post Translational Modifications ◽  
Regulatory Aspects ◽  
Dolichyl Phosphate ◽  
Complex Membrane ◽  
Secretory Glycoproteins ◽  
Membrane Components ◽  
Polypeptide Chains

From the time of their synthesis in the rough endoplasmic reticulum until they are secreted, packaged in lysosomes, or appear as membrane components at the cell surface, the polypeptide chains of N - and O -linked glycoproteins remain associated with intracellular membranes that are components of the secretory pathway. The various co-translational and post-translational modifications of the carbohydrate moieties of glycoproteins have been shown to occur within morphologically and functionally distinct regions of this complex membrane system. However, the sugar nucleotides, which serve as precursors to the oligosaccharide moieties of these glycoproteins, are synthesized almost exclusively in the cytoplasm. These findings raise a number of questions about the mechanisms involved in the transmembrane assembly of membrane and secretory glycoproteins. In this paper these questions are reviewed and recent studies directed towards providing answers to them are summarized. In addition, information related to the possible role of dolichyl phosphate in regulating the glycosylation of proteins is presented.

scholarly journals The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation

2017 ◽  
Vol 474 (4) ◽  
pp. 445-469 ◽  
Author(s):  
G. Michael Preston ◽  
Jeffrey L. Brodsky
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Integral Membrane Proteins ◽  
26S Proteasome ◽  
Polyubiquitin Chain ◽  
Post Translational Modifications ◽  
Cytoplasmic Face ◽  
And Control ◽  
Ubiquitination Machinery

The endoplasmic reticulum (ER) serves as a warehouse for factors that augment and control the biogenesis of nascent proteins entering the secretory pathway. In turn, this compartment also harbors the machinery that responds to the presence of misfolded proteins by targeting them for proteolysis via a process known as ER-associated degradation (ERAD). During ERAD, substrates are selected, modified with ubiquitin, removed from the ER, and then degraded by the cytoplasmic 26S proteasome. While integral membrane proteins can directly access the ubiquitination machinery that resides in the cytoplasm or on the cytoplasmic face of the ER membrane, soluble ERAD substrates within the lumen must be retrotranslocated from this compartment. In either case, nearly all ERAD substrates are tagged with a polyubiquitin chain, a modification that represents a commitment step to degrade aberrant proteins. However, increasing evidence indicates that the polyubiquitin chain on ERAD substrates can be further modified, serves to recruit ERAD-requiring factors, and may regulate the ERAD machinery. Amino acid side chains other than lysine on ERAD substrates can also be modified with ubiquitin, and post-translational modifications that affect substrate ubiquitination have been observed. Here, we summarize these data and provide an overview of questions driving this field of research.

Self-Regulatory Aspects of Bullshitting and Bullshit Detection

2020 ◽  
Vol 51 (4) ◽  
pp. 239-253
Author(s):  
John V. Petrocelli ◽  
Haley F. Watson ◽  
Edward R. Hirt
Keyword(s):  
Evidence Based ◽  
Regulatory Aspects

Abstract. Two experiments investigate the role of self-regulatory resources in bullshitting behavior (i.e., communicating with little to no regard for evidence, established knowledge, or truth; Frankfurt, 1986 ; Petrocelli, 2018a ), and receptivity and sensitivity to bullshit. It is hypothesized that evidence-based communication and bullshit detection require motivation and considerably greater self-regulatory resources relative to bullshitting and insensitivity to bullshit. In Experiment 1 ( N = 210) and Experiment 2 ( N = 214), participants refrained from bullshitting only when they possessed adequate self-regulatory resources and expected to be held accountable for their communicative contributions. Results of both experiments also suggest that people are more receptive to bullshit, and less sensitive to detecting bullshit, under conditions in which they possess relatively few self-regulatory resources.

scholarly journals System-wide identification and prioritization of enzyme substrates by thermal analysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Amir Ata Saei ◽  
Christian M. Beusch ◽  
Pierre Sabatier ◽  
Juan Astorga Wells ◽  
Hassan Gharibi ◽  
...  
Keyword(s):  
Thermal Analysis ◽  
Thioredoxin Reductase ◽  
Structural Level ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Enzyme Substrate ◽  
Thioredoxin Reductase 1 ◽  
Enzyme Substrates ◽  
Substrate Proteins

AbstractDespite the immense importance of enzyme–substrate reactions, there is a lack of general and unbiased tools for identifying and prioritizing substrate proteins that are modified by the enzyme on the structural level. Here we describe a high-throughput unbiased proteomics method called System-wide Identification and prioritization of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that the enzymatic post-translational modification of substrate proteins is likely to change their thermal stability. In our proof-of-concept studies, SIESTA successfully identifies several known and novel substrate candidates for selenoprotein thioredoxin reductase 1, protein kinase B (AKT1) and poly-(ADP-ribose) polymerase-10 systems. Wider application of SIESTA can enhance our understanding of the role of enzymes in homeostasis and disease, opening opportunities to investigate the effect of post-translational modifications on signal transduction and facilitate drug discovery.

scholarly journals Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 995
Author(s):  
Xiaoyan Hou ◽  
Lijun Qiao ◽  
Ruijuan Liu ◽  
Xuechao Han ◽  
Weifang Zhang
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Mtor Pathway ◽  
Cycle Progression ◽  
Post Translational Modifications ◽  
Hpv E7 ◽  
Cycle Regulation

Persistent infection of high-risk human papillomavirus (HR-HPV) plays a causal role in cervical cancer. Regulator of chromosome condensation 1 (RCC1) is a critical cell cycle regulator, which undergoes a few post-translational modifications including phosphorylation. Here, we showed that serine 11 (S11) of RCC1 was phosphorylated in HPV E7-expressing cells. However, S11 phosphorylation was not up-regulated by CDK1 in E7-expressing cells; instead, the PI3K/AKT/mTOR pathway promoted S11 phosphorylation. Knockdown of AKT or inhibition of the PI3K/AKT/mTOR pathway down-regulated phosphorylation of RCC1 S11. Furthermore, S11 phosphorylation occurred throughout the cell cycle, and reached its peak during the mitosis phase. Our previous data proved that RCC1 was necessary for the G1/S cell cycle progression, and in the present study we showed that the RCC1 mutant, in which S11 was mutated to alanine (S11A) to mimic non-phosphorylation status, lost the ability to facilitate G1/S transition in E7-expressing cells. Moreover, RCC1 S11 was phosphorylated by the PI3K/AKT/mTOR pathway in HPV-positive cervical cancer SiHa and HeLa cells. We conclude that S11 of RCC1 is phosphorylated by the PI3K/AKT/mTOR pathway and phosphorylation of RCC1 S11 facilitates the abrogation of G1 checkpoint in HPV E7-expressing cells. In short, our study explores a new role of RCC1 S11 phosphorylation in cell cycle regulation.

scholarly journals Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

2020 ◽  
Vol 22 (1) ◽  
pp. 323
Author(s):  
Ramesh Kumar ◽  
Divya Mehta ◽  
Nimisha Mishra ◽  
Debasis Nayak ◽  
Sujatha Sunil
Keyword(s):  
Rna Virus ◽  
Viral Proteins ◽  
Post Translational Modification ◽  
Host Proteins ◽  
Viral Protein Synthesis ◽  
Post Translational Modifications ◽  
Small Proteins ◽  
Cellular Machinery ◽  
Chemical Groups

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins’ functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.

scholarly journals A history of uremic toxicity and of the European Uremic Toxin Work Group (EUTox)

2021 ◽  
Author(s):  
Raymond Vanholder ◽  
Angel Argiles ◽  
Joachim Jankowski ◽  
Keyword(s):  
Work Group ◽  
Target Identification ◽  
Kidney Injury ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Post Translational Modifications ◽  
History Of ◽  
Advanced Stages ◽  
Uremic Syndrome

Abstract The uremic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease (CKD) resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uremic toxins. Here, we describe the historical evolution of the scientific knowledge about uremic toxins and the role played in this process by the European Uremic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uremic toxin goes back to the early 17th century when the existence of what later would appear to be urea was recognized. It cost about two further centuries to better define the role of urea and its link to kidney failure and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when Insights grew exponentially, coincides with the foundation and activity of EUTox. In the final section we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes, and toxin characteristics in acute kidney injury and transplantation.

scholarly journals Histone Modifying Enzymes in Gynaecological Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 816
Author(s):  
Priya Ramarao-Milne ◽  
Olga Kondrashova ◽  
Sinead Barry ◽  
John D. Hooper ◽  
Jason S. Lee ◽  
...  
Keyword(s):  
Genome Instability ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Driver Mutations ◽  
Promoter Regions ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
Cancer Types ◽  
Histone Modifying Enzymes

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.

scholarly journals Phosphorylation of the Regulators, a Complex Facet of NF-κB Signaling in Cancer

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 15
Author(s):  
Aishat Motolani ◽  
Matthew Martin ◽  
Mengyao Sun ◽  
Tao Lu
Keyword(s):  
Transcription Factor ◽  
Cardiovascular Diseases ◽  
Cancer Progression ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Malignant Diseases ◽  
Future Perspectives ◽  
Post Translational Modifications ◽  
Site Specific

The nuclear factor kappa B (NF-κB) is a ubiquitous transcription factor central to inflammation and various malignant diseases in humans. The regulation of NF-κB can be influenced by a myriad of post-translational modifications (PTMs), including phosphorylation, one of the most popular PTM formats in NF-κB signaling. The regulation by phosphorylation modification is not limited to NF-κB subunits, but it also encompasses the diverse regulators of NF-κB signaling. The differential site-specific phosphorylation of NF-κB itself or some NF-κB regulators can result in dysregulated NF-κB signaling, often culminating in events that induce cancer progression and other hyper NF-κB related diseases, such as inflammation, cardiovascular diseases, diabetes, as well as neurodegenerative diseases, etc. In this review, we discuss the regulatory role of phosphorylation in NF-κB signaling and the mechanisms through which they aid cancer progression. Additionally, we highlight some of the known and novel NF-κB regulators that are frequently subjected to phosphorylation. Finally, we provide some future perspectives in terms of drug development to target kinases that regulate NF-κB signaling for cancer therapeutic purposes.

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