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The Science of the Total Environment Sep 2023Dibutyl phthalate (DBP) is a typical plasticizer and is widely used in industrial manufacturing. DBP has been reported to be cardiotoxic, manifested by oxidative stress...
Dibutyl phthalate (DBP) is a typical plasticizer and is widely used in industrial manufacturing. DBP has been reported to be cardiotoxic, manifested by oxidative stress and inflammatory damage. However, the potential mechanism of heart damage caused by DBP remains unclear. By in vivo and in vitro experiments, first, this study demonstrated that DBP induced endoplasmic reticulum (ER) stress, mitochondrial damage, and pyroptosis in cardiomyocytes; second, it was confirmed that the ER stress increased mitochondrial-associated ER membrane (MAM), which led to mitochondrial damage by abnormalizing Ca transfer within MAMs; finally, it was confirmed that mitochondrial reactive oxygen species (mtROS) production was increased after mitochondrial damage, which activated NLRP3 inflammasome and pyroptosis in cardiomyocytes. In summary, ER stress is the initiation of DBP cardiotoxicity, which leads to mitochondrial damage by disrupting Ca transfer from ER to mitochondria. Subsequently, released mtROS promotes the activation of NLRP3 inflammasome and pyroptosis, eventually leading to heart damage.
Topics: Humans; Dibutyl Phthalate; Pyroptosis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Mitochondria; Endoplasmic Reticulum; Heart Injuries
PubMed: 37270010
DOI: 10.1016/j.scitotenv.2023.164620 -
International Journal of Molecular... Dec 2023Maintenance of proteome integrity is essential for cell function and survival in changing cellular and environmental conditions. The endoplasmic reticulum (ER) is the... (Review)
Review
Maintenance of proteome integrity is essential for cell function and survival in changing cellular and environmental conditions. The endoplasmic reticulum (ER) is the major site for the synthesis of secretory and membrane proteins. However, the accumulation of unfolded or misfolded proteins can perturb ER protein homeostasis, leading to ER stress and compromising cellular function. Eukaryotic organisms have evolved sophisticated and conserved protein quality control systems to ensure protein folding fidelity via the unfolded protein response (UPR) and to eliminate potentially harmful proteins via ER-associated degradation (ERAD) and ER-phagy. In this review, we summarize recent advances in our understanding of the mechanisms of ER protein homeostasis in plants and discuss the crosstalk between different quality control systems. Finally, we will address unanswered questions in this field.
Topics: Proteostasis; Unfolded Protein Response; Endoplasmic Reticulum Stress; Endoplasmic Reticulum; Plants; Membrane Proteins
PubMed: 38139432
DOI: 10.3390/ijms242417599 -
Autophagy Oct 2023The autophagic machinery is highly conserved in eukaryotes. Plants, as sessile organisms, are more susceptible to environmental stresses than animals. Autophagy plays a...
The autophagic machinery is highly conserved in eukaryotes. Plants, as sessile organisms, are more susceptible to environmental stresses than animals. Autophagy plays a pivotal role in plant stress responses, but the regulation of autophagic flux in plants remains enigmatic with few autophagic receptors identified. We recently characterized an E3 ligase, the ubiquitin-fold modifier 1 (Ufm1) ligase 1 (Ufl1), as well as its small modifier protein Ufm1, as interactors of the core autophagy-related (ATG) proteins. Mutants of these ufmylation system components are hypersensitive to salt stress and trigger the upregulation of endoplasmic reticulum (ER) stress-responsive genes, as well as the accumulation of ER sheets caused by a defect in reticulophagy. Increased expression of Ufl1, Ufm1 and Ufm1-conjugating enzyme 1 (Ufc1) are also triggered by salt stress in plants. This study identified and demonstrated the participation of ufmylation components in maintaining ER homeostasis by regulating reticulophagy under salt stress in plants.: ATG, autophagy-related; ER, endoplasmic reticulum; LIR, LC3-interacting region; ROS, reactive oxygen species; CDK5RAP3/C53, CDK5 regulatory subunit-associated protein 3; Uba5, Ufm1-activating enzyme 5; Ufc1, Ufm1-conjugating enzyme 1; Ufl1, Ufm1 ligase 1; Ufm1, ubiquitin-fold modifier 1; UPR, unfolded protein response.
Topics: Arabidopsis; Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Plant Proteins; Plants; Salt Stress; Ubiquitin-Protein Ligases
PubMed: 37126567
DOI: 10.1080/15548627.2023.2203985 -
Cell Reports Aug 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates in human cells by interacting with host factors following infection. To understand the virus and...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates in human cells by interacting with host factors following infection. To understand the virus and host interactome proximity, we introduce a super-resolution proximity labeling (SR-PL) method with a "plug-and-playable" PL enzyme, TurboID-GBP (GFP-binding nanobody protein), and we apply it for interactome mapping of SARS-CoV-2 ORF3a and membrane protein (M), which generates highly perturbed endoplasmic reticulum (ER) structures. Through SR-PL analysis of the biotinylated interactome, 224 and 272 peptides are robustly identified as ORF3a and M interactomes, respectively. Within the ORF3a interactome, RNF5 co-localizes with ORF3a and generates ubiquitin modifications of ORF3a that can be involved in protein degradation. We also observe that the SARS-CoV-2 infection rate is efficiently reduced by the overexpression of RNF5 in host cells. The interactome data obtained using the SR-PL method are presented at https://sarscov2.spatiomics.org. We hope that our method will contribute to revealing virus-host interactions of other viruses in an efficient manner.
Topics: Humans; SARS-CoV-2; COVID-19; Antiviral Agents; Membrane Proteins; Endoplasmic Reticulum
PubMed: 37478010
DOI: 10.1016/j.celrep.2023.112835 -
Experimental Cell Research Oct 2023Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is... (Review)
Review
Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is essential for the exchange of metabolites and their communication. These functional apposition sites are termed membrane contact sites. Dynamic membrane contact sites between various sub-cellular structures such as mitochondria, endoplasmic reticulum, peroxisomes, Golgi apparatus, lysosomes, lipid droplets, plasma membrane, endosomes, etc. have been reported in various model systems. The burgeoning area of research on membrane contact sites has witnessed several manuscripts in recent years that identified the contact sites and components involved. Several methods have been developed to identify, measure and analyze the membrane contact sites. In this manuscript, we aim to discuss important methods developed to date that are used to study membrane contact sites.
Topics: Mitochondrial Membranes; Mitochondria; Cell Membrane; Endoplasmic Reticulum; Endosomes
PubMed: 37633408
DOI: 10.1016/j.yexcr.2023.113756 -
The EMBO Journal Sep 2023Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded...
Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER-embedded RING finger protein 26 (RNF26) at the C-terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis.
Topics: Intermediate Filaments; Proteotoxic Stress; Vimentin; Endoplasmic Reticulum Stress; Endoplasmic Reticulum; Autophagy
PubMed: 37519262
DOI: 10.15252/embj.2022111252 -
Clinical and Translational Medicine Nov 2023The study and synthesis of membrane organelles are becoming increasingly important, not only as simplified cellular models for corresponding molecular and metabolic... (Review)
Review
BACKGROUND
The study and synthesis of membrane organelles are becoming increasingly important, not only as simplified cellular models for corresponding molecular and metabolic studies but also for applications in synthetic biology of artificial cells and drug delivery vehicles. Lipid droplets (LDs) are central organelles in cellular lipid metabolism and are involved in almost all metabolic processes. Multiple studies have also demonstrated a high correlation between LDs and metabolic diseases. During these processes, LDs reveal a highly dynamic character, with their lipid fraction, protein composition and subcellular localisation constantly changing in response to metabolic demands. However, the molecular mechanisms underlying these functions have not been fully understood due to the limitations of cell biology approaches. Fortunately, developments in synthetic biology have provided a huge breakthrough for metabolism research, and methods for in vitro synthesis of LDs have been successfully established, with great advances in protein binding, lipid function, membrane dynamics and enzymatic reactions.
AIMS AND METHODS
In this review, we provide a comprehensive overview of the assembly and function of endogenous LDs, from the generation of lipid molecules to how they are assembled into LDs in the endoplasmic reticulum. In particular, we highlight two major classes of synthetic LD models for fabrication techniques and their recent advances in biology and explore their roles and challenges in achieving real applications of artificial LDs in the future.
Topics: Humans; Lipid Droplets; Lipid Metabolism; Endoplasmic Reticulum; Lipids; Metabolic Diseases
PubMed: 37997538
DOI: 10.1002/ctm2.1441 -
Genes and Immunity Dec 2023Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a proteolytic enzyme involved in adaptive immunity. The ERAP2 gene is highly polymorphic and encodes haplotypes that... (Review)
Review
Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a proteolytic enzyme involved in adaptive immunity. The ERAP2 gene is highly polymorphic and encodes haplotypes that confer resistance against lethal infectious diseases, but also increase the risk for autoimmune disorders. Identifying how ERAP2 influences susceptibility to these traits requires an understanding of the selective pressures that shaped and maintained allelic variation throughout human evolution. Our review discusses the genetic regulation of haplotypes and diversity in naturally occurring ERAP2 allotypes in the global population. We outline how these ERAP2 haplotypes evolved during human history and highlight the presence of Neanderthal DNA sequences in ERAP2 of modern humans. Recent evidence suggests that human adaptation during the last ~10,000 years and historic pandemics left a significant mark on the ERAP2 gene that determines susceptibility to infectious and inflammatory diseases today.
Topics: Humans; Aminopeptidases; Autoimmune Diseases; Endoplasmic Reticulum; Haplotypes; Minor Histocompatibility Antigens; Evolution, Molecular; Adaptive Immunity
PubMed: 37925533
DOI: 10.1038/s41435-023-00225-8 -
Parasite Immunology Nov 2023Alteration in the physiological state of the endoplasmic reticulum (ER) leads to the specific response known as unfolded protein response (UPR) or ER stress response.... (Review)
Review
Alteration in the physiological state of the endoplasmic reticulum (ER) leads to the specific response known as unfolded protein response (UPR) or ER stress response. The UPR is driven by three sensor proteins, namely: Inositol-Requiring Enzyme 1, Protein Kinase RNA-like ER kinase and Activating Transcription Factor 6 to restore ER homeostasis. Pathogenic infection can initiate UPR activation; some pathogens can subvert the UPR to promote their survival and replication. Many intracellular pathogens, including Leishmania, can interact and hijack ER for their survival and replication, triggering ER stress and subsequently ER stress response. This review aims to provide a comprehensive overview of the ER stress response in infections with the Leishmania species.
Topics: Animals; Unfolded Protein Response; Endoplasmic Reticulum Stress; Leishmaniasis; Endoplasmic Reticulum; Leishmania
PubMed: 37571855
DOI: 10.1111/pim.13009 -
Journal of Molecular Biology Jul 2024It has been estimated that up to one-third of the proteins encoded by the human genome enter the endoplasmic reticulum (ER) as extended polypeptide chains where they... (Review)
Review
It has been estimated that up to one-third of the proteins encoded by the human genome enter the endoplasmic reticulum (ER) as extended polypeptide chains where they undergo covalent modifications, fold into their native structures, and assemble into oligomeric protein complexes. The fidelity of these processes is critical to support organellar, cellular, and organismal health, and is perhaps best underscored by the growing number of disease-causing mutations that reduce the fidelity of protein biogenesis in the ER. To meet demands encountered by the diverse protein clientele that mature in the ER, this organelle is populated with a cadre of molecular chaperones that prevent protein aggregation, facilitate protein disulfide isomerization, and lower the activation energy barrier of cis-trans prolyl isomerization. Components of the lectin (glycan-binding) chaperone system also reside within the ER and play numerous roles during protein biogenesis. In addition, the ER houses multiple homologs of select chaperones that can recognize and act upon diverse peptide signatures. Moreover, redundancy helps ensure that folding-compromised substrates are unable to overwhelm essential ER-resident chaperones and enzymes. In contrast, the ER in higher eukaryotic cells possesses a single member of the Hsp70, Hsp90, and Hsp110 chaperone families, even though several homologs of these molecules reside in the cytoplasm. In this review, we discuss specific functions of the many factors that maintain ER quality control, highlight some of their interactions, and describe the vulnerabilities that arise from the absence of multiple members of some chaperone families.
Topics: Endoplasmic Reticulum; Humans; Molecular Chaperones; Protein Folding; Homeostasis; Animals
PubMed: 38143019
DOI: 10.1016/j.jmb.2023.168418