Much to know about proteolysis: intricate proteolytic machineries compromise essential cellular functions

2008 ◽  
Vol 36 (5) ◽  
pp. 781-785 ◽  
Author(s):  
Gemma Marfany ◽  
Rosa Farràs ◽  
Eduardo Salido ◽  
Dimitris P. Xirodimas ◽  
Manuel S. Rodríguez
Keyword(s):  
Protein Complexes ◽  
Ubiquitin Proteasome System ◽  
Cellular Functions ◽  
Cell Functions ◽  
Starting Point ◽  
Wide Range ◽  
Cellular Factors ◽  
Ubiquitin Proteasome ◽  
The University ◽  
Intracellular Proteolysis

Proteolysis has traditionally been considered as a radical way to terminate the function of a protein. However, protein destruction also is the starting point for many processes as they can only occur when the way has been cleared for the action of other proteins. Protein destruction can occur virtually in all compartments and organelles of the cell, associated with cell membranes or large protein complexes, it determines subcellular partitioning, association with positive or negative regulators which conditions the action of many critical cellular factors. The third intracellular proteolysis meeting held by the University La Laguna, Canary Islands, Spain, included speakers working with some of the most important proteolytic systems present in higher eukaryotes, such as the UPS (ubiquitin–proteasome system) and autophagy. Owing to the fact that these pathways directly or indirectly regulate many cell functions, this meeting brought together an audience with a wide range of research interests, including genetic, cell biological, biochemical and structural aspects of protein degradation. Some of these topics inspired interesting discussions and a significant number of these are developed in the issues reviewed herein.

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals Dramatic performance ofClostridium thermocellumexplained by its wide range of cellulase modalities

2016 ◽  
Vol 2 (2) ◽  
pp. e1501254 ◽  
Author(s):  
Qi Xu ◽  
Michael G. Resch ◽  
Kara Podkaminer ◽  
Shihui Yang ◽  
John O. Baker ◽  
...  
Keyword(s):  
Cell Wall ◽  
Bacterial Cell ◽  
Mode Of Action ◽  
Protein Complexes ◽  
Cellulose Degradation ◽  
Bacterial Cell Wall ◽  
Cellular Functions ◽  
Gene Deletions ◽  
Wide Range ◽  
Biomass Particles

Clostridium thermocellumis the most efficient microorganism for solubilizing lignocellulosic biomass known to date. Its high cellulose digestion capability is attributed to efficient cellulases consisting of both a free-enzyme system and a tethered cellulosomal system wherein carbohydrate active enzymes (CAZymes) are organized by primary and secondary scaffoldin proteins to generate large protein complexes attached to the bacterial cell wall. This study demonstrates thatC. thermocellumalso uses a type of cellulosomal system not bound to the bacterial cell wall, called the “cell-free” cellulosomal system. The cell-free cellulosome complex can be seen as a “long range cellulosome” because it can diffuse away from the cell and degrade polysaccharide substrates remotely from the bacterial cell. The contribution of these two types of cellulosomal systems inC. thermocellumwas elucidated by characterization of mutants with different combinations of scaffoldin gene deletions. The primary scaffoldin, CipA, was found to play the most important role in cellulose degradation byC. thermocellum, whereas the secondary scaffoldins have less important roles. Additionally, the distinct and efficient mode of action of theC. thermocellumexoproteome, wherein the cellulosomes splay or divide biomass particles, changes when either the primary or secondary scaffolds are removed, showing that the intact wild-type cellulosomal system is necessary for this essential mode of action. This new transcriptional and proteomic evidence shows that a functional primary scaffoldin plays a more important role compared to secondary scaffoldins in the proper regulation of CAZyme genes, cellodextrin transport, and other cellular functions.

scholarly journals p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shasha Tao ◽  
Pengfei Liu ◽  
Gang Luo ◽  
Montserrat Rojo de la Vega ◽  
Heping Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Complexes ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Client Proteins

ABSTRACT Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

scholarly journals Phosphoinositide-derived messengers in endocrine signaling

2006 ◽  
Vol 188 (2) ◽  
pp. 135-153 ◽  
Author(s):  
T Balla
Keyword(s):  
Protein Complexes ◽  
Modern Concept ◽  
Cellular Functions ◽  
Surface Receptors ◽  
Cell Functions ◽  
Molecular Events ◽  
Membrane Compartments ◽  
Specific Receptors ◽  
Endocrine Signaling ◽  
G Protein Coupled

One of the fundamental questions in endocrinology is how circulating or locally produced hormones affect target cell functions by activating specific receptors linked to numerous signal-transduction pathways. An important subset of G protein-coupled cell-surface receptors can activate phospholipase C enzymes to hydrolyze a small but critically important class of phospholipids, the phosphoinositides. Although this signaling pathway has been extensively explored over the last 20 years, this has proven to be only the tip of the iceberg, and the multiplicity and diversity of the cellular functions controlled by phosphoinositides have surpassed any imagination. Phosphoinositides have been found to be key regulators of ion channels and transporters, and controllers of vesicular trafficking and the transport of lipids between intracellular membranes. Essentially, they organize the recruitment and regulation of signaling protein complexes in specific membrane compartments. While many of these processes have been classically studied by cell biologists, molecular endocrinology cannot ignore these recent advances, and now needs to integrate the cell biologist’s views in the modern concept of how hormones affect cell functions and how derailment of simple molecular events can lead to complex endocrine and metabolic disorders.

scholarly journals Strategies for the identification of ubiquitin ligase inhibitors

2010 ◽  
Vol 38 (1) ◽  
pp. 132-136 ◽  
Author(s):  
Seth J. Goldenberg ◽  
Jeffrey G. Marblestone ◽  
Michael R. Mattern ◽  
Benjamin Nicholson
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Therapeutic Strategy ◽  
Ubiquitin Proteasome System ◽  
Advantages And Disadvantages ◽  
Wide Range ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Effective Therapeutic Strategy ◽  
Protein Ligases

Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; however, toxicity with this target remains high. E3s (Ub–protein ligases) represent an alternative attractive therapeutic target in the UPS. In this paper, we will discuss current platforms that report on E3 ligase activity and can detect E3 inhibitors, and underline the advantages and disadvantages of each approach.

scholarly journals Propuesta de Comunicación con Tecnología Óptica Pasiva en el Reparto “Carlos Manuel de Céspedes” de Bayamo, Cuba: opción de estudio para los universitarios

2017 ◽  
Vol 1 (8) ◽  
Author(s):  
Manleys Rodríguez Torres ◽  
Randy Verdecia Peña
Keyword(s):  
Access Network ◽  
University Student ◽  
Housing Sector ◽  
Power Budget ◽  
Starting Point ◽  
Wide Range ◽  
La Red ◽  
The University ◽  
Estudiantes Universitarios

El objetivo del trabajo consistió en diseñar una propuesta de comunicación para el reparto Carlos Manuel de Céspedes de Bayamo, Granma, Cuba. Para ello se tomó como campo investigativo 10 entidades y 1 061. Esta se basa en el despliegue de fibra óptica en el reparto en cuestión partiendo de la reutilización de la red de acceso existente. Dicho proyecto puede ser tomado como material de estudio por estudiantes universitarios. En la proposición de comunicación se concibe la inclusión de 9 MDU para dar servicios al sector residencial y 10 MDU para el sector empresarial, además, se incluye un splitter 1:32 y una OLT que se ubicaran en el sitio tecnológico y en el centro telefónico más cercano respectivamente. Para la marcha exitosa del trabajo se utilizaron métodos teóricos. La calidad de la propuesta de comunicación se verificó mediante el cálculo del presupuesto de potencia óptica, donde inciden las pérdidas provocadas por el equipamiento a utilizar. Se concluyó que con esta investigación se logra eliminar la demanda insatisfecha y permite que los clientes en sentido general puedan tener servicios de internet de banda ancha.  Palabras claves: Fibra óptica, sector residencial, sector empresarial, presupuesto de potencia, demanda insatisfecha, centro telefónico, sitio tecnológico   A proposal of communication with passive optic technology in the section “Carlos Manuel de Céspedes” of Bayamo, Cuba: an option of study for the university students Abstract  The objective of the work consisted in designing a communicative proposal in the section “Carlos Manuel de Cespedes”, in Bayamo, Cuba. There were taken 10 enterprises as the field researching as well as 1 061 s houses. It is based in the spread of optic fiber in that section taking as starting point the re-using of the existing access network. This project can be taken as a material fo studying the university student. In the proposal of communication it is glanced the inclution of 9 MDU to give service to the housing sector and 10 MDU for enterprises, it is also included 1:32 splitter and OLT that will be located in the technological place and in the closed telephone center. Fort he successful trend of the work there were used some theoratical methods, the quality of the proposal of communication was verified through the calculus budget of optic power, where the roduced power joint together collapse. It was concluded that with this research it is achieved to eliminated the unccessful demand it permits the overall users could have internet services wide range.  Keywords: optical fiber, housing sector, enterprise sector, power budget, unccessful demand, telephone center, technological place

scholarly journals A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Liam Baird ◽  
Tadayuki Tsujita ◽  
Eri H. Kobayashi ◽  
Ryo Funayama ◽  
Takeshi Nagashima ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcriptional Regulation ◽  
Ubiquitin Proteasome System ◽  
Conditional Knockout ◽  
Protein Homeostasis ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Inducible Systems

ABSTRACT Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

Targeting the Ubiquitin-proteasome System for the Treatment of Multiple Myeloma and Other Human Diseases

2010 ◽  
Vol 2 ◽  
pp. CMT.S2889
Author(s):  
Klaus Podar ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Human Diseases ◽  
Cellular Functions ◽  
Adverse Side Effects ◽  
Ubiquitin Proteasome ◽  
Novel Approaches

The ubiquitin-proteasome-degradation system plays a key role in multiple cellular functions. Its deregulation is associated with the initiation and progression of human diseases including not only solid and hematologic malignancies but also neurologic and autoimmune disorders. This article discusses several novel mechanistic aspects of the ubiquitin-proteasome system. Moreover, it focuses on the development, mechanisms of action, and clinical experience with Bortezomib, the first in-class-proteasome inhibitor to enter the clinics. Finally, it summarizes novel approaches to specifically target distinct components within the highly complex and dynamic ubiquitin-proteasome machinery to ultimately further increase drug activity, as well as reduce drug resistance and adverse side effects.

Targeting of host-cell ubiquitin pathways by viruses

2005 ◽  
Vol 41 ◽  
pp. 139-156 ◽  
Author(s):  
Julia Shackelford ◽  
Joseph S. Pagano
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Cell Signalling ◽  
Ubiquitin Proteasome System ◽  
Life Cycles ◽  
Therapeutic Interventions ◽  
Signalling Pathways ◽  
Cellular Functions ◽  
Ubiquitin Proteasome ◽  
Do So

The ability of viruses to co-opt cell signalling pathways has, over millions of years of co-evolution, come to pervade nearly every facet of cellular functions. Recognition of the extent to which the ubiquitin–proteasome system can be directed or subverted by viruses is relatively recent. Viral products interact with, and adjust, the ubiquitin–proteasome machinery precisely and at many levels, and they do so at distinct stages of viral life-cycles. The implications for both cells and viruses are fundamental, and understanding viral strategies in this context opens up fascinating new areas for research that span from basic cell biology to therapeutic interventions against both viruses and malignancies.

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