scholarly journals An HRD/DER-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport

2002 ◽  
Vol 158 (1) ◽  
pp. 91-102 ◽  
Author(s):  
Cole M. Haynes ◽  
Sabrina Caldwell ◽  
Antony A. Cooper
Keyword(s):  
Ubiquitin Ligase ◽  
Degradation Kinetics ◽  
Ubiquitin Proteasome System ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
Ubiquitin Proteasome ◽  
Type Rate ◽  
Quality Control Mechanism ◽  
The Unfolded Protein Response ◽  
Protein Response

We have identified a new pathway of ER-associated degradation in Saccharomyces cerevisiae that functions separately from the HRD/DER pathway comprised of Hrd1p, Hrd3p, Der1p, and Ubc7p. This pathway, termed Hrd1p independent-proteolysis (HIP), is capable of recognizing and degrading both lumenal (CPY* and PrA*), and integral membrane proteins (Sec61–2p) that misfold in the ER. CPY* overexpression likely saturates the HRD/DER pathway and activates the HIP pathway, so the slowed degradation kinetics of CPY* in a hrd1Δ strain is restored to a wild-type rate when CPY* is overexpressed. Substrates of HIP require vesicular trafficking between the ER and Golgi apparatus before degradation by the ubiquitin-proteasome system. Ubiquitination of HIP substrates does not involve the HRD/DER pathway ubiquitin ligase Hrd1p, but instead uses another ubiquitin ligase, Rsp5p. HIP is regulated by the unfolded protein response as Ire1p is necessary for the degradation of CPY* when overexpressed, but not when CPY* is expressed at normal levels. Both the HIP and HRD/DER pathways contribute to the degradation of CPY*, and only by eliminating both is CPY* degradation completely blocked.

scholarly journals BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress

2019 ◽  
Vol 218 (9) ◽  
pp. 3002-3018 ◽  
Author(s):  
Fei-Yun Chen ◽  
Min-Yu Huang ◽  
Yu-Min Lin ◽  
Chi-Huan Ho ◽  
Shu-Yu Lin ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Fate ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Unfolded Protein ◽  
Ubiquitin Proteasome ◽  
Cellular Stresses ◽  
The Unfolded Protein Response ◽  
Protein Response

The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin–proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α–XBP1s–ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.

Concordance of Several Subcellular Interactions Initiates Alzheimer’s Dementia: Their Reversal Requires Combination Treatment

2017 ◽  
Vol 32 (3) ◽  
pp. 166-181 ◽  
Author(s):  
W. J. Fessel
Keyword(s):  
Combination Treatment ◽  
Ubiquitin Proteasome System ◽  
Signaling System ◽  
Factors Affecting ◽  
Unfolded Protein ◽  
Single Drug ◽  
Ubiquitin Proteasome ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Subcellular Level

The pathogenesis of Alzheimer’s disease involves multiple pathways that, at the macrolevel, include decreased proliferation plus increased loss affecting neurons, astrocytes, and capillaries and, at the subcellular level, involve several elements: amyloid/amyloid precursor protein, presenilins, the unfolded protein response, the ubiquitin/proteasome system, the Wnt/catenin system, the Notch signaling system, mitochondria, mitophagy, calcium, and tau. Data presented show the intimate, anatomical interactions between neurons, astrocytes, and capillaries; the interactions between the several subcellular factors affecting those cells; and the treatments that are currently available and that might correct dysfunctions in the subcellular factors. Available treatments include lithium, valproate, pioglitazone, erythropoietin, and prazosin. Since the subcellular pathogenesis involves multiple interacting elements, combination treatment would be more effective than administration of a single drug directed at only 1 element. The overall purpose of this presentation is to describe the pathogenesis in detail and to explain the proposed treatments.

scholarly journals ER stress causes widespread protein aggregation and prion formation

2017 ◽  
Vol 216 (8) ◽  
pp. 2295-2304 ◽  
Author(s):  
Norfadilah Hamdan ◽  
Paraskevi Kritsiligkou ◽  
Chris M. Grant
Keyword(s):  
Protein Aggregation ◽  
Er Stress ◽  
Secretory Pathway ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

scholarly journals Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Dmitri Shcherbakov ◽  
Youjin Teo ◽  
Heithem Boukari ◽  
Adrian Cortes-Sanchon ◽  
Matilde Mantovani ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Mitochondrial Biogenesis ◽  
Protein Quality ◽  
Genetic Manipulation ◽  
Ubiquitin Proteasome System ◽  
Limiting Factor ◽  
Unfolded Protein ◽  
Comprehensive Picture ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10−4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

scholarly journals Brucella effector hijacks endoplasmic reticulum quality control machinery to prevent premature egress

2019 ◽  
Author(s):  
Jean-Baptiste Luizet ◽  
Julie Raymond ◽  
Thais Lourdes Santos Lacerda ◽  
Magali Bonici ◽  
Frédérique Lembo ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
Type Iv ◽  
Endoplasmic Reticulum Quality Control ◽  
Fine Regulation ◽  
Infected Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractPerturbation of endoplasmic reticulum (ER) functions can have critical consequences for cellular homeostasis. An elaborate surveillance system known as ER quality control (ERQC) ensures that only correctly assembled proteins reach their destination. Persistence of misfolded or improperly matured proteins upregulates the unfolded protein response (UPR) to cope with stress, activates ER associated degradation (ERAD) for delivery to proteasomes for degradation. We have identified a Brucella abortus type IV secretion system effector called BspL that targets Herp, a key component of ERQC and is able to augment ERAD. Modulation of ERQC by BspL results in tight control of the kinetics of autophagic Brucella-containing vacuole formation, preventing premature bacterial egress from infected cells. This study highlights how bacterial pathogens may hijack ERAD components for fine regulation of their intracellular trafficking.

scholarly journals Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Karina Cuanalo-Contreras ◽  
Abhisek Mukherjee ◽  
Claudio Soto
Keyword(s):  
Protein Misfolding ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Unfolded Protein ◽  
Natural Defense ◽  
Dependent Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself.

scholarly journals The Endoplasmic Reticulum Role in the Plant Response to Abiotic Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Sofía Reyes-Impellizzeri ◽  
Adrian A. Moreno
Keyword(s):  
Endoplasmic Reticulum ◽  
Plant Response ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
A Cell ◽  
Client Proteins ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact ◽  
S Proteins

The endoplasmic reticulum (ER) is the organelle where one third of the proteins of a cell are synthetized. Several of these proteins participate in the signaling and response of cells, tissues, or from the organism to the environment. To secure the proper synthesis and folding of these proteins, or the disposal of unfolded or misfolded proteins, the ER has different mechanisms that interact and regulate each other. These mechanisms are known as the ER quality control (ERQC), ER-associated degradation (ERAD) and the unfolded protein response (UPR), all three participants of the maintenance of ER protein homeostasis or proteostasis. Given the importance of the client proteins of these ER mechanisms in the plant response to the environment, it is expected that changes or alterations on their components have an impact on the plant response to environmental cues or stresses. In this mini review, we focus on the impact of the alteration of components of ERQC, ERAD and UPR in the plant response to abiotic stresses such as drought, heat, osmotic, salt and irradiation. Also, we summarize findings from recent publications looking for a connection between these processes and their possible client(s) proteins. From this, we observed that a clear connection has been established between the ERAD and UPR mechanisms, but evidence that connects ERQC components to these both processes or their possible client(s) proteins is still lacking. As a proposal, we suggest the use of proteomics approaches to uncover the identity of these proteins and their connection with ER proteostasis.

scholarly journals Negative modulation of macroautophagy by HERPUD1 is counteracted by an increased ER-lysosomal network with impact in drug-induced stress cell survival

2021 ◽  
Author(s):  
Gabriela Vargas ◽  
Omar Humberto Cortes ◽  
Eloisa Natalia Arias-Munoz ◽  
Sergio Felipe Hernandez-Galaz ◽  
Cristobal Cerda-Troncoso ◽  
...  
Keyword(s):  
Cell Survival ◽  
Ubiquitin Proteasome System ◽  
Drug Induced ◽  
Unfolded Protein ◽  
Membrane Contact Sites ◽  
Nutritional Deprivation ◽  
Ubiquitin Proteasome ◽  
Negative Role ◽  
And Function ◽  
Protein Response

Macroautophagy and the ubiquitin proteasome system work as an interconnected network in the maintenance of cellular homeostasis. Indeed, efficient activation of macroautophagy upon nutritional deprivation is sustained by degradation of preexisting proteins by the proteasome. However, the specific substrates that are degraded by the proteasome in order to activate macroautophagy are currently unknown. By quantitative proteomic analysis we identified several proteins downregulated in response to starvation but independently of ATG5 expression. Among them, the most significant was HERPUD1, an ER protein of short-half life and a well-known substrate of the proteasome. We found that increased HERPUD1 stability by deletion of its ubiquitin-like domain (UBL) plays a negative role on basal and induced macroautophagy. Moreover, we found it triggers ER expansion by reordering the ER in crystalloid structures, but in the absence of unfolded protein response activation. Surprisingly, we found ER expansion led to an increase in the number and function of lysosomes establishing a tight network with the presence of membrane-contact sites. Importantly, a phosphomimetic S59D mutation within the UBL mimics UBL deletion on its stability and the ER-lysosomal network expansion revealing an increase of cell survival under stress conditions. Altogether, we propose stabilized HERPUD1 downregulates macroautophagy favoring instead a closed interplay between the ER and lysosomes with consequences in cell stress survival.

scholarly journals SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

2021 ◽  
Author(s):  
Pascal Demange ◽  
Etienne Joly ◽  
Julien Marcoux ◽  
Patrick R. A. Zanon ◽  
Dymytrii Listunov ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Agents ◽  
Control Mechanisms ◽  
Proof Of Concept ◽  
Unfolded Protein ◽  
Ubiquitin Proteasome ◽  
Protein Response ◽  
Cytotoxic Mechanism

ABSTRACTHundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs. Graphical abstract

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