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Trends in Cell Biology Jul 2018Interorganellar contacts are increasingly recognized as central to the control of cellular behavior. These contacts, which typically involve a small fraction of the... (Review)
Review
Interorganellar contacts are increasingly recognized as central to the control of cellular behavior. These contacts, which typically involve a small fraction of the endomembrane surface, are local communication hubs that resemble synapses. We propose the term contactology to denote the analysis of interorganellar contacts. Endoplasmic reticulum (ER) contacts with mitochondria were recognized several decades ago; major roles in ion and lipid transfer, signaling, and membrane dynamics have been established, while others continue to emerge. The functional diversity of ER-mitochondrial (ER-mito) contacts is mirrored in their structural heterogeneity, with subspecialization likely supported by multiple, different linker-forming protein structures. The nanoscale size of the contacts has made studying their structure, function, and dynamics difficult. This review focuses on the structure of the ER-mito contacts, methods for studying them, and the roles of contacts in Ca and reactive oxygen species (ROS) signaling.
Topics: Animals; Calcium; Endoplasmic Reticulum; Humans; Mitochondria; Reactive Oxygen Species; Signal Transduction
PubMed: 29588129
DOI: 10.1016/j.tcb.2018.02.009 -
Annual Review of Pathology 2015Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the... (Review)
Review
Numerous genetic and environmental insults impede the ability of cells to properly fold and posttranslationally modify secretory and transmembrane proteins in the endoplasmic reticulum (ER), leading to a buildup of misfolded proteins in this organelle--a condition called ER stress. ER-stressed cells must rapidly restore protein-folding capacity to match protein-folding demand if they are to survive. In the presence of high levels of misfolded proteins in the ER, an intracellular signaling pathway called the unfolded protein response (UPR) induces a set of transcriptional and translational events that restore ER homeostasis. However, if ER stress persists chronically at high levels, a terminal UPR program ensures that cells commit to self-destruction. Chronic ER stress and defects in UPR signaling are emerging as key contributors to a growing list of human diseases, including diabetes, neurodegeneration, and cancer. Hence, there is much interest in targeting components of the UPR as a therapeutic strategy to combat these ER stress-associated pathologies.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Unfolded Protein Response
PubMed: 25387057
DOI: 10.1146/annurev-pathol-012513-104649 -
EMBO Reports Aug 2022Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to... (Review)
Review
Eukaryotic cells adequately control the mass and functions of organelles in various situations. Autophagy, an intracellular degradation system, largely contributes to this organelle control by degrading the excess or defective portions of organelles. The endoplasmic reticulum (ER) is an organelle with distinct structural domains associated with specific functions. The ER dynamically changes its mass, components, and shape in response to metabolic, developmental, or proteotoxic cues to maintain or regulate its functions. Therefore, elaborate mechanisms are required for proper degradation of the ER. Here, we review our current knowledge on diverse mechanisms underlying selective autophagy of the ER, which enable efficient degradation of specific ER subdomains according to different demands of cells.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Macroautophagy
PubMed: 35758175
DOI: 10.15252/embr.202255192 -
Cellular and Molecular Life Sciences :... Jan 2016The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The... (Review)
Review
The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
Topics: Animals; Calcium; Endoplasmic Reticulum; Fertilization; Humans; Lipid Metabolism; Mitosis; Protein Biosynthesis; Protein Folding; Proteins; Signal Transduction; Unfolded Protein Response
PubMed: 26433683
DOI: 10.1007/s00018-015-2052-6 -
International Journal of Molecular... Dec 2022Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments,... (Review)
Review
Besides protein processing, the endoplasmic reticulum (ER) has several other functions such as lipid synthesis, the transfer of molecules to other cellular compartments, and the regulation of Ca homeostasis. Before leaving the organelle, proteins must be folded and post-translationally modified. Protein folding and revision require molecular chaperones and a favorable ER environment. When in stressful situations, ER luminal conditions or chaperone capacity are altered, and the cell activates signaling cascades to restore a favorable folding environment triggering the so-called unfolded protein response (UPR) that can lead to autophagy to preserve cell integrity. However, when the UPR is disrupted or insufficient, cell death occurs. This review examines the links between UPR signaling, cell-protective responses, and death following ER stress with a particular focus on those mechanisms that operate in neurons.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Signal Transduction; Cell Death; Molecular Chaperones
PubMed: 36499512
DOI: 10.3390/ijms232315186 -
Cell Death & Disease Oct 2023Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role... (Review)
Review
Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors.
Topics: Endoplasmic Reticulum Stress; Autophagy; Endoplasmic Reticulum; Mitophagy; Cell Death
PubMed: 37794028
DOI: 10.1038/s41419-023-06154-8 -
The FEBS Journal Jan 2019The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production... (Review)
Review
The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Signal Transduction; Unfolded Protein Response
PubMed: 30027602
DOI: 10.1111/febs.14608 -
Molecular Cell Dec 2023The cytoplasm is highly compartmentalized, but the extent and consequences of subcytoplasmic mRNA localization in non-polarized cells are largely unknown. We determined...
The cytoplasm is highly compartmentalized, but the extent and consequences of subcytoplasmic mRNA localization in non-polarized cells are largely unknown. We determined mRNA enrichment in TIS granules (TGs) and the rough endoplasmic reticulum (ER) through particle sorting and isolated cytosolic mRNAs by digitonin extraction. When focusing on genes that encode non-membrane proteins, we observed that 52% have transcripts enriched in specific compartments. Compartment enrichment correlates with a combinatorial code based on mRNA length, exon length, and 3' UTR-bound RNA-binding proteins. Compartment-biased mRNAs differ in the functional classes of their encoded proteins: TG-enriched mRNAs encode low-abundance proteins with strong enrichment of transcription factors, whereas ER-enriched mRNAs encode large and highly expressed proteins. Compartment localization is an important determinant of mRNA and protein abundance, which is supported by reporter experiments showing that redirecting cytosolic mRNAs to the ER increases their protein expression. In summary, the cytoplasm is functionally compartmentalized by local translation environments.
Topics: Endoplasmic Reticulum; Proteins; Cytosol; RNA, Messenger; Protein Transport; Protein Biosynthesis
PubMed: 38134885
DOI: 10.1016/j.molcel.2023.11.025 -
International Journal of Molecular... May 2022Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of approximately 10,000 different soluble and membrane proteins of human cells,...
Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of approximately 10,000 different soluble and membrane proteins of human cells, which amounts to about 30% of the proteome [...].
Topics: Endoplasmic Reticulum; Humans; Membrane Proteins; Protein Transport
PubMed: 35628123
DOI: 10.3390/ijms23105315 -
American Journal of Physiology. Cell... Jan 2020The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of... (Review)
Review
The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 "interactome" and discuss the pathological and physiological role of such AGR2 interactions.
Topics: Animals; Endoplasmic Reticulum; Humans; Mucoproteins; Multiprotein Complexes; Oncogene Proteins; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction
PubMed: 31644305
DOI: 10.1152/ajpcell.00532.2018