Unfolded Protein Response Mechanisms Research Articles

Translocational attenuation mediated by the PERK-SRP14 axis is a protective mechanism of unfolded protein response

The unfolded protein response (UPR) relieves endoplasmic reticulum (ER) stress through multiple strategies, including reducing protein synthesis, increasing protein folding capabilities, and enhancing misfolded protein degradation. After a multi-omics analysis, we find that signal recognition particle 14 (SRP14), an essential component of the SRP, is markedly reduced in cells undergoing ER stress. Further experiments indicate that SRP14 reduction requires PRKR-like ER kinase (PERK)-mediated eukaryotic translation initiation factor 2α (eIF2α) phosphorylation but is independent of ATF4 or ATF3 transcription factors. The decrease of SRP14 correlates with reduced translocation of fusion proteins and endogenous cathepsin D. Enforced expression of an SRP14 variant with elongation arrest capability prevents the reduced translocation of cathepsin D in stressed cells, whereas an SRP14 mutant without the activity does not. Finally, overexpression of SRP14 augments the UPR and aggravates ER-stress-induced cell death. These data suggest that translocational attenuation mediated by the PERK-SRP14 axis is a protective measure for the UPR to mitigate ER stress.

Oscillations in Neuronal Activity: A Neuron-Centered Spatiotemporal Model of the Unfolded Protein Response in Prion Diseases.

Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress, triggering the Unfolded Protein Response (UPR), which slows or stops protein translation and can indirectly reduce the toxic load. However, the UPR may also trigger processes leading to apoptotic cell death and the UPR is implicated in the progression of several NDs. In this paper, we develop a novel mathematical model to describe the spatiotemporal dynamics of the UPR mechanism for prion diseases. Our model is centered around a single neuron, with representative proteins P (healthy) and S (toxic) interacting with heterodimer dynamics (S interacts with P to form two S's). The model takes the form of a coupled system of nonlinear reaction-diffusion equations with a delayed, nonlinear flux for P (delay from the UPR). Through the delay, we find parameter regimes that exhibit oscillations in the P- and S-protein levels. We find that oscillations are more pronounced when the S-clearance rate and S-diffusivity are small in comparison to the P-clearance rate and P-diffusivity, respectively. The oscillations become more pronounced as delays in initiating the UPR increase. We also consider quasi-realistic clinical parameters to understand how possible drug therapies can alter the course of a prion disease. We find that decreasing the production of P, decreasing the recruitment rate, increasing the diffusivity of S, increasing the UPR S-threshold, and increasing the S clearance rate appear to be the most powerful modifications to reduce the mean UPR intensity and potentially moderate the disease progression.

The Combinatorial Effect of Ad-IL-24 and Ad-HSV-tk/GCV on Tumor Size, Autophagy, and UPR Mechanisms in Multiple Myeloma Mouse Model.

Multiple myeloma is a type of malignant neoplasia whose treatment has changed over the past decade. This study aimed to investigate the effects of combination of Adenovector-carrying interleukin-24 and herpes simplex virus 1 thymidine kinase/ganciclovir on tumor growth, autophagy, and unfolded protein response mechanisms in mouse model of multiple myeloma.Six groups of mice, including Ad-HSV-tk/GCV, Ad-IL-24, Ad-HSV-tk/IL-24, Ad-GFP, and positive and negative controls, were investigated, and each group was injected every 72 h. The tumor size was measured several times. The expression of LC3B evaluated through western blotting and ASK-1, CHOP, Caspase-3, and ATF-6 genes in the UPR and apoptosis pathways were also analyzed by the quantitative polymerase chain reaction (qPCR) method.The present results showed that the injection of Ad-HSV-tk/GCV, Ad-HSV-tk/IL-24, and metformin reduced the tumor size. The expression of LC3B was significantly higher in the treatment groups and positive control groups compared to the negative control group. The expression of CHOP, caspase-3, and ATF-6 genes was significantly higher in the Ad-IL-24 group compared to the other treatment groups. Besides, the ASK-1 expression was significantly lower in the Ad-IL-24 group as compared to the other groups. Overall, the results indicated that the presence of the HSV-tk gene in the adenovectors reduced the size of tumors and induced autophagy by triggering the expression of LC3B protein. The presence of the IL-24 might affect tumor growth but not as much the therapeutic effect of HSV-tk. Furthermore, the results indicated that co-administration of IL-24 and HSV-tk had no synergistic effect on tumor size control.

Review of ER stress and unfolded protein response

The cell is the fundamental unit of life, and all of the organelles within it perform essential tasks. Cells must meet their typical requirements for survival and development in order to contribute to the functioning of living things. Protein folding in the rough ER, the major organelle for the synthesis, folding, and modification of secreted and transmembrane proteins, is essential for their proper function in the cytoplasm. Endoplasmic reticulum stress (ERS) occurs when the protein-folding capacity of this organelle is disrupted due to various external causes or intracellular events, resulting to a buildup of misfolded or unfolded proteins. Concerns in this area are possible. Some illnesses, cell death, and metabolic abnormalities are examples. The cell's stress response mechanism is the unfolded protein response (UPR). Reduced translation, degradation of unfolded proteins to reduce damage, and increased production of cell-mate proteins all aid in the folding of nascent proteins. This research uses a literature review approach to learn about the ER, an experiment on ER Stress, the reaction mechanism of unfolded protein response (UPR), diseases induced by ER Stress, and the significance of UPR in these illnesses.

Fundamental and Applicative Aspects of the Unfolded Protein Response in Yeasts.

Upon the dysfunction or functional shortage of the endoplasmic reticulum (ER), namely, ER stress, eukaryotic cells commonly provoke a protective gene expression program called the unfolded protein response (UPR). The molecular mechanism of UPR has been uncovered through frontier genetic studies using Saccharomyces cerevisiae as a model organism. Ire1 is an ER-located transmembrane protein that directly senses ER stress and is activated as an RNase. During ER stress, Ire1 promotes the splicing of HAC1 mRNA, which is then translated into a transcription factor that induces the expression of various genes, including those encoding ER-located molecular chaperones and protein modification enzymes. While this mainstream intracellular UPR signaling pathway was elucidated in the 1990s, new intriguing insights have been gained up to now. For instance, various additional factors allow UPR evocation strictly in response to ER stress. The UPR machineries in other yeasts and fungi, including pathogenic species, are another important research topic. Moreover, industrially beneficial yeast strains carrying an enforced and enlarged ER have been produced through the artificial and constitutive induction of the UPR. In this article, we review canonical and up-to-date insights concerning the yeast UPR, mainly from the viewpoint of the functions and regulation of Ire1 and HAC1.

Prognostic Role of Unfolded Protein Response-Related Genes in Hepatocellular Carcinoma.

To reveal the prognostic role of unfolded protein response (UPR) -related genes in hepatocellular carcinoma (HCC). Hepatocellular carcinoma is a genetically heterogeneous tumor, and the prediction of its prognosis remains a challenge. Studies elucidating the molecular mechanisms of UPR have rapidly increased. However, the UPR molecular subtype characteristics of the related genes in HCC progression have yet to be thoroughly studied. Conducting a comprehensive assessment of the prognostic signature of genes related to the UPR in patients with HCC can advance our understanding of the cellular processes contributing to the progression of HCC and offer innovative strategies in precise therapy. Based on the gene expression profiles associated with UPR in HCC, we explored the molecular subtypes mediated by UPR-related genes and constructed a UPR-related genes signature that could precisely predict the prognosis for HCC. Using microarray data of HCC patients, differentially expressed UPR-related genes (DEGs) were discovered in malignancies and normal tissues. The HCC was classified into two molecular subtypes by the NMF algorithm based on DEGs modification of the UPR. Moreover, we developed a UPR-related model for predicting HCC patients' prognosis. The robustness of the UPR-related model was confirmed in external validation. Moreover, we analyzed immune responses in different risk groups. Analysis of immune functions revealed that Treg, Macrophages, aDCs, and MHC class-I were significantly up-regulated in high-risk HCC. At the same time, cytolytic activity and type I and II INF response were higher in a low-risk subgroup. This study identified two UPR molecular subtypes of HCC and developed a ten-gene HCC prognostic signature model (EXTL3, PPP2R5B, ZBTB17, CCT3, CCT4, CCT5, GRPEL2, HSP90AA1, PDRG1, and STC2), which can robustly forecast the progression of HCC.

Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress.

The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease. We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells. Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines. We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.

Effects of Spatial Expression of Activating Transcription Factor 4 on the Pathogenicity of Two Phenotypes of Bovine Viral Diarrhea Virus by Regulating the Endoplasmic Reticulum-Mediated Autophagy Process.

The endoplasmic reticulum (ER) stress response is a highly conserved stress-defense mechanism and activates the adaptive unfolded protein response (UPR) to mitigate imbalance. The ER stress-activated signaling pathways can also trigger autophagy to facilitate cellular repair. Bovine viral diarrhea virus (BVDV) utilizes the host cellular ER as the primary site of the life cycle. However, the interplay between cellular ER stress and BVDV replication remains unclear. This report reveals that cytopathic (cp) and noncytopathic (ncp) BVDV have distinct strategies to regulate UPR mechanisms and ER stress-mediated autophagy for their own benefit. Immunoblot analysis revealed that cp and ncp BVDV differentially regulated the abundance of ER chaperone GRP78 for viral replication, while the protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2 subunit α (eIF2α)-activating transcription factor 4 (ATF4) pathway of the UPR was switched on at different stages of infection. Pretreatment with ER stress inducer promoted virion replication, but RNA interference (RNAi) knockdown of ATF4 in BVDV-infected cells significantly attenuated BVDV infectivity titers. More importantly, the effector ATF4 activated by cp BVDV infection translocated into the nucleus to mediate autophagy, but ATF4 was retained in the cytoplasm during ncp BVDV infection. In addition, we found that cp BVDV core protein was localized in the ER to induce ER stress-mediated autophagy. Overall, the potential therapeutic target ATF4 may contribute to the global eradication campaign of BVDV. IMPORTANCE The ER-tropic viruses hijack the host cellular ER as the replication platform of the life cycle, which can lead to strong ER stress. The UPR and related transcriptional cascades triggered by ER stress play a crucial role in viral replication and pathogenesis, but little is known about these underlying mechanisms. Here, we report that cytopathic and noncytopathic BVDV use different strategies to reprogram the cellular UPR and ER stress-mediated autophagy for their own advantage. The cytopathic BVDV unconventionally downregulated the expression level of GRP78, creating perfect conditions for self-replication via the UPR, and the noncytopathic BVDV retained ATF4 in the cytoplasm to provide an advantage for its persistent infection. Our findings provide new insights into exploring how BVDV and other ER-tropic viruses reprogram the UPR signaling pathway in the host cells for replication and reveal the attractive host target ATF4 for new antiviral agents.

Progesterone regulates the endoplasmic reticulum-associated degradation and Unfolded Protein Response axis by mimicking the androgenic stimulation in prostate cancer cells.

Today, androgen receptor(AR)-mediated signaling mechanisms in prostate cancer are intensively studied. However, the roles of other steroid hormones in prostate cancer and their effects on androgenic signaling still remain a mystery. Recent studies focused on the androgen-mediated regulation of protein quality control mechanisms such as endoplasmic reticulum-associated degradation (ERAD) and unfolded protein response (UPR) in prostate cancer cells. Present study, we investigated the action of progesterone signaling on ERAD and UPR mechanisms and analyzed the crosstalk of progesterone signaling with androgenic signal in prostate cancer cells. The mode of action of progesterone on ERAD, UPR and AR signaling in prostate cancer was investigated by cell culture studies using LNCaP and 22Rv1 cells. To this aim qRT-PCR, western-blotting assay, immunofluorescent microscopy, nuclear fractionation and bioinformatic analysis were used. Our results indicated that progesterone positively regulates mRNA and protein levels of ERAD components in LNCaP cells. Also, it induced the IRE⍺ and PERK branches of UPR signaling. Progesterone receptor antagonist effectively antagonized the progesterone-induced responses. We also had similar results in 22Rv1cells. Also,we tested the effect of the pharmacologically reducing of IRE⍺ and PERK signaling on progesterone-induced ERAD. Additionally, we determined the presence of putative progesterone response elements(PREs) in the promoter regions of ERAD members by bioinformatic tool. More strikingly, we found progesterone regulates AR signaling by modulating the nuclear transactivation of AR. Herein, we defined that progesterone hormone positively regulates ERAD and UPR mechanisms in prostate cancer cells and that progesterone contributes to the molecular biology of prostate cancer by regulating androgenic signaling. Mode of Action of Progesteron on Androgen sensitive prostate cancer cells.

The role and mechanism of unfolded protein response signaling pathway in methylmercury-induced apoptosis of mouse spermatocytes germ cell-2 cells.

The study aimed to explore the role and mechanism of unfolded protein response (UPR) in methylmercury (MeHg)-induced Mouse Spermatocytes (GC-2spd[ts]) apoptosis. Methods such as MTT, flow cytometry, and Western Blot were used to evaluate the cell viability, membrane potential (MMP), reactive oxygen species (ROS), calcium ion (Ca2+ ), rate of cell apoptosis, and the expression of apoptosis-related and UPR-related protein. The results showed that with the increase of MeHg concentration, cell viability and MMP decreased, ROS, Ca2+ , rate of cell apoptosis, and the expression of apoptosis-related protein and UPR-related protein increased. To further explore the effect of ROS-induced oxidative damage on it, the ROS inhibitor N-acetyl-L-cysteine (NAC) was used. The effects of MeHg on germ cell (GC-2) cells were partially inhibited after NAC pretreatment. Our present study proved that MeHg might induce cell apoptosis by activating the UPR signaling pathway in GC-2 cells and affect normal reproductive function.

A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders

Astrocytes are one of the most numerous glial cells in the central nervous system (CNS) and provide essential support to neurons to ensure CNS health and function. During a neuropathological challenge, such as during human immunodeficiency virus (HIV)-1 infection or (METH)amphetamine exposure, astrocytes shift their neuroprotective functions and can become neurotoxic. Identifying cellular and molecular mechanisms underlying astrocyte dysfunction are of heightened importance to optimize the coupling between astrocytes and neurons and ensure neuronal fitness against CNS pathology, including HIV-1-associated neurocognitive disorders (HAND) and METH use disorder. Mitochondria are essential organelles for regulating metabolic, antioxidant, and inflammatory profiles. Moreover, endoplasmic reticulum (ER)-associated signaling pathways, such as calcium and the unfolded protein response (UPR), are important messengers for cellular fate and function, including inflammation and mitochondrial homeostasis. Increasing evidence supports that the three arms of the UPR are involved in the direct contact and communication between ER and mitochondria through mitochondria-associated ER membranes (MAMs). The current study investigated the effects of HIV-1 infection and chronic METH exposure on astrocyte ER and mitochondrial homeostasis and then examined the three UPR messengers as potential regulators of astrocyte mitochondrial dysfunction. Using primary human astrocytes infected with pseudotyped HIV-1 or exposed to low doses of METH for 7 days, astrocytes had increased mitochondrial oxygen consumption rate (OCR), cytosolic calcium flux and protein expression of UPR mediators. Notably, inositol-requiring protein 1α (IRE1α) was most prominently upregulated following both HIV-1 infection and chronic METH exposure. Moreover, pharmacological inhibition of the three UPR arms highlighted IRE1α as a key regulator of astrocyte metabolic function. To further explore the regulatory role of astrocyte IRE1α, astrocytes were transfected with an IRE1α overexpression vector followed by activation with the proinflammatory cytokine interleukin 1β. Overall, our findings confirm IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake, highlighting a novel potential target for regulating astrocyte dysfunction. Finally, these findings suggest both canonical and non-canonical UPR mechanisms of astrocyte IRE1α. Thus, additional studies are needed to determine how to best balance astrocyte IRE1α functions to both promote astrocyte neuroprotective properties while preventing neurotoxic properties during CNS pathologies.

Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative proteinopathic disease. The deposits of misfolded Amyloid β and Tau proteins in the brain of patients with AD suggest an imbalance in endoplasmic reticulum (ER) proteostasis. ER stress is due to accumulation of aberrant proteins in the ER lumen, which then leads to activation of three sensor protein pathways that ultimately evokes the adaptive mechanism of the unfolded protein response (UPR). The UPR mechanism operates via adaptive UPR and the apoptotic UPR. Adaptive UPR tries to restore imbalance in ER hemostasis by decreasing protein production, enhanced chaperone involvement to restore protein folding, misfolded protein decay by proteasome, and suppression of ribosomal translation ultimately relieving the excessive protein load in the ER. Subsequently, apoptotic UPR activated under severe ER stress conditions triggers cell death. MicroRNAs (miRNAs) are small non-coding protein causing dysregulated translational of mRNAs in a sequential manner. They are considered to be critical elements in the maintenance of numerous cellular activities, hemostasis, and developmental processes. Therefore, upregulation or downregulation of miRNA expression is implicated in several pathogenic processes. Evidence from scientific studies suggest a strong correlation between ERUPR signaling and miRNA dysregulation but the research done is still dormant. In this review, we summarized the cross-talk between ER stress, and the UPR signaling processes and their role in AD pathology by scrutinizing and collecting information from original research and review articles.

Unfolded protein response alleviates acid-induced premature senescence by promoting autophagy in nucleus pulposus cells.

Acid-induced cellular senescence is a critical underlying mechanism of intervertebral disc (IVD) degeneration (IDD). Acid stimulation activates a variety of biological changes including autophagy, endoplasmic reticulumstress, and related unfolded protein response (UPR), which are important regulators of cellular senescence. However, the precise mechanism of acid-mediated UPR and autophagy in nucleus pulposus cell (NPC) senescence has not been fully elucidated. In this study, we used acid to mimic the acidic microenvironment of IVD, and rat NPCs were cultured with or without autophagy or UPR signaling small-interfering RNAs. The related proteins and genes were assessed by immunofluorescence staining assay, Western blot analyses, and quantitative real-time polymerase chain reactionto monitor the activation of these signals and classify the molecular mechanisms underlying the correlation between autophagy and UPR pathway. Cell cycle analyses, senescence-associated β-galactosidase staining, gene expression, and immunoblotting analyses were performed to observe NPC senescence. Results showed that acid stimulation not only induced NPC senescence, but also initiated UPR and autophagy. Silencing the binding immunoglobulin proteinsignaling of UPR or autophagy signaling promoted rat NPC senescence. Knock-down of the UPR also blocked NPC autophagy. Taken together, UPR inhibits NPC senescence under acidic condition by activating autophagy. Hence, UPR-dependent autophagy could be an effective biologic target for the treatment of IDD in the future.

The disturbance of protein synthesis/degradation homeostasis is a common trait of age-related neurodegenerative disorders.

Protein homeostasis or "proteostasis" represent the process that regulates the balance of the intracellular functional and "healthy" proteins. Proteostasis is fundamental to preserve physiological metabolic processes in the cell and it allow to respond to any given stimulus as the expression of components of the proteostasis network is customized according to the proteomic demands of different cellular environments. In conditions that promote unfolding/misfolding of proteins chaperones act as signaling molecules inducing extreme measures to either fix the problem or destroy unfolded proteins. When the chaperone machinery fails under pathological insults unfolded proteins induce the endoplasmic reticulum (ER) stress activating the unfolded protein response (UPR) machinery. The activation of the UPR restores ER proteostasis primarily through the transcriptional remodeling of ER protein folding, trafficking, and degradation pathways, such as the ubiquitin proteasome system (UPS). If these mechanisms do not manage to clear the aberrant proteins, proteasome overload and become defective, and misfolded proteins may form aggregates thus extending the UPR mechanism. These aggregates are then attempted to be cleared by macroautophagy. Impaired proteostasis promote the accumulation of misfolded proteins that exacerbate the damage to chaperones, surveillance systems and/or degradative activities. Remarkably, the removal of toxic misfolded proteins is critical for all cells, but it is especially significant in neurons since these cannot be readily replaced. In neurons, the maintenance of efficient proteostasis is essential to healthy aging since the dysregulation of the proteostasis network can lead to neurodegenerative disease. Each of these brain pathologies is characterized by the repeated misfolding of one of more peculiar proteins, which evade both the protein folding machinery and cellular degradation mechanisms and begins to form aggregates that nucleate out into large fibrillar aggregates. In this chapter we describe the mechanisms, associated with faulty proteostasis, that promote the formation of protein aggregates, amyloid fibrils, intracellular, and extracellular inclusions in the most common nondegenerative disorders also referred to as protein misfolding disorders.

Identification of a novel signature based on unfolded protein response-related gene for predicting prognosis in bladder cancer

BackgroundThe unfolded protein response (UPR) served as a vital role in the progression of tumors, but the molecule mechanisms of UPR in bladder cancer (BLCA) have been not fully investigated.MethodsWe identified differentially expressed unfolded protein response-related genes (UPRRGs) between BLCA samples and normal bladder samples in the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis and the least absolute shrinkage and selection operator penalized Cox regression analysis were used to construct a prognostic signature in the TCGA set. We implemented the validation of the prognostic signature in GSE13507 from the Gene Expression Omnibus database. The ESTIMATE, CIBERSORT, and ssGSEA algorithms were used to explore the correlation between the prognostic signature and immune cells infiltration as well as key immune checkpoints (PD-1, PD-L1, CTLA-4, and HAVCR2). GDSC database analyses were conducted to investigate the chemotherapy sensitivity among different groups. GSEA analysis was used to explore the potential mechanisms of UPR-based signature.ResultsA prognostic signature comprising of seven genes (CALR, CRYAB, DNAJB4, KDELR3, CREB3L3, HSPB6, and FBXO6) was constructed to predict the outcome of BLCA. Based on the UPRRGs signature, the patients with BLCA could be classified into low-risk groups and high-risk groups. Patients with BLCA in the low-risk groups showed the more favorable outcomes than those in the high-risk groups, which was verified in GSE13507 set. This signature could serve as an autocephalous prognostic factor in BLCA. A nomogram based on risk score and clinical characteristics was established to predict the over survival of BLCA patients. Furthermore, the signature was closely related to immune checkpoints (PD-L1, CTLA-4, and HAVCR2) and immune cells infiltration including CD8+ T cells, follicular helper T cells, activated dendritic cells, and M2 macrophages. GSEA analysis indicated that immune and carcinogenic pathways were enriched in high-risk group.ConclusionsWe identified a novel unfolded protein response-related gene signature which could predict the over survival, immune microenvironment, and chemotherapy response of patients with bladder cancer.

The Endoplasmic Reticulum Role in the Plant Response to Abiotic Stress.

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.

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses.

The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.

Unfolded protein response (UPR) mediated under heat stress in plants

Drastic fluctuation in temperature during crop growth challenges its yield to a greater extent, thus diminishing the agricultural productivity globally. At the cellular level, protein homeostasis is altered or disturbed directly or indirectly by the high temperature. Improper protein folding due to heat stress creates ER stress in the endoplasmic reticulum (ER). In order to balance the protein folding demand and its capacity and to maintain ER homeostasis, cells activate unfolded protein response (UPR), as a homeostatic mechanism. The transcription factors, bZip60 and bZip28/17 have been reported as the key modules of UPR for alleviating ER stress. Despite UPR mechanisms has been extensively investigated, the intervention of heat stress with ER homeostasis remains unclear. This review summarizes the key findings on this potential nexus. Additionally, the link between ER associated degradation and plant growth regulators during heat stress were also addressed.

Research Progress of the UPR Mechanism and its Effect on Improving Foreign Protein Expression.

The unfolded protein response (UPR) is a protective mechanism against endoplasmic reticulum (ER) stress that induces a series of signal transduction pathways to eliminate misfolded proteins. The UPR mechanism is highly conserved in fungi, higher organisms, plants and mammals. The UPR pathway is activated to stabilize ER functions when there are too many unfolded proteins or misfolded proteins in the ER. However, stress continues when ER proteins are stimulated by toxic substances that affect the balance of the UPR pathway, which causes changes in the structure and function of the ER and other organelles. These ultimately disrupt homeostasis in the body and cause pathological reactions that can be fatal. The UPR mechanism has clear effects on stabilizing the protein-folding environment. Dysfunction or disruption of the UPR mechanism is associated with numerous disorders, including neurodegenerative diseases, loss of control of protein secretion, cerebral ischemia and epilepsy, neuropsychiatric diseases, eye diseases, skin diseases, metabolic and inflammatory diseases, atherosclerosis, and heart disease. Thus, characterization of UPR function and its dysfunction has significant importance and has broad application prospects, which make research into the UPR a research hotspot.

Molecular Mechanisms of ER Stress and UPR in the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease involving aggregation of misfolded proteins inside the neuron causing prolonged cellular stress. The neuropathological hallmarks of AD include the formation of senile plaques and neurofibrillary tangles in specific brain regions that lead to synaptic loss and neuronal death. The exact mechanism of neuron dysfunction in AD remains obscure. In recent years, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal degeneration seen in AD. Apart from AD, many other diseases also involve misfolded proteins aggregations in the ER, a condition referred to as ER stress. The response of the cell to ER stress is to activate a group of signaling pathways called unfolded protein response (UPR) that stimulates a particular transcriptional program to restore ER function and ensure cell survival. ER stress also involves the generation of reactive oxygen species (ROS) that, together with mitochondrial ROS and decreased effectiveness of antioxidant mechanisms, producing a condition of chronic oxidative stress. The unfolded proteins may not always produce a response that leads to the restoration of cellular functions, but they may also lead to inflammation by a set of different pathways with deleterious consequences. In this review, we extensively discuss the role of ER stress and how to target it using different pharmacological approaches in AD development and onset.