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Progress in Molecular and Subcellular... 2021The endoplasmic reticulum, as the site of synthesis for proteins in the secretory pathway has evolved select machineries to ensure the correct folding and modification...
The endoplasmic reticulum, as the site of synthesis for proteins in the secretory pathway has evolved select machineries to ensure the correct folding and modification of proteins. However, sometimes these quality control mechanisms fail and proteins are misfolded. Other factors, such as nutrient deprivation, hypoxia or an increased demand on protein synthesis can also cause the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. There are mechanisms that recognise and deal with this accumulation of protein through degradation and/or export. Many diseases are associated with aberrant quality control mechanisms, and among these, cancer has emerged as a group of diseases that rely on endoplasmic reticulum homeostasis to sustain development and growth. The knowledge of how protein quality control operates in cancer has identified opportunities for these pathways to be pharmacologically targeted, which could lead to newer or more effective treatments in the future.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Neoplasms; Protein Folding; Proteostasis
PubMed: 34050868
DOI: 10.1007/978-3-030-67696-4_10 -
Biochimica Et Biophysica Acta Mar 2004Proteins of the Bcl-2 family are important regulators of cell fate. The role of these proteins in controlling mitochondrial apoptotic processes has been extensively... (Review)
Review
Proteins of the Bcl-2 family are important regulators of cell fate. The role of these proteins in controlling mitochondrial apoptotic processes has been extensively investigated, although exact molecular mechanisms are incompletely understood. However, mounting evidence indicates that these proteins also function at the endoplasmic reticulum and other locations within the cell. Both pro- and anti-apoptotic Bcl-2 family members can regulate endoplasmic reticulum calcium, cellular pH and endoplasmic reticulum resident proteins. In this review, we discuss the activities and potential targets of Bcl-2 family members at the endoplasmic reticulum and other cellular locations.
Topics: Animals; Apoptosis; Calcium; Endoplasmic Reticulum; Mitochondria; Mutation; Proto-Oncogene Proteins c-bcl-2
PubMed: 14996496
DOI: 10.1016/j.bbamcr.2003.07.001 -
Environmental Microbiology Reports Jun 2021The normal functioning of eukaryotic cells depends on the compartmentalization of metabolic processes within specific organelles. Interactions among organelles, such as... (Review)
Review
The normal functioning of eukaryotic cells depends on the compartmentalization of metabolic processes within specific organelles. Interactions among organelles, such as those between the endoplasmic reticulum (ER) - considered the largest single structure in eukaryotic cells - and other organelles at membrane contact sites (MCSs) have also been suggested to trigger synergisms, including intracellular immune responses against pathogens. In addition to the ER-endogenous functions and ER-organelle MCSs, we present the perspective of a third-order role of the ER as a host contact site for endosymbiotic microbial non-pathogens and pathogens, from endosymbiont bacteria to parasitic protists and viruses. Although understudied, ER-endosymbiont interactions have been observed in a range of eukaryotic hosts, including protists, plants, algae, and metazoans. Host ER interactions with endosymbionts could be an ER function built from ancient, conserved mechanisms selected for communicating with mutualistic endosymbionts in specific life cycle stages, and they may be exploited by pathogens and parasites. The host ER-'guest' interactome and traits in endosymbiotic biology are briefly discussed. The acknowledgment and understanding of these possible mechanisms might reveal novel evolutionary perspectives, uncover the causes of unexplained cellular disorders and suggest new pharmacological targets.
Topics: Bacteria; Biological Evolution; Endoplasmic Reticulum; Humans; Symbiosis; Virus Diseases
PubMed: 33559322
DOI: 10.1111/1758-2229.12938 -
Annual Review of Biochemistry 2013Looks can be deceiving. Although peroxisomes appear to be simple organelles, their formation and maintenance pose unique challenges for the cell. The birth of new... (Review)
Review
Looks can be deceiving. Although peroxisomes appear to be simple organelles, their formation and maintenance pose unique challenges for the cell. The birth of new peroxisomes starts at the endoplasmic reticulum (ER), which delivers lipids and membrane proteins. To form a new peroxisomal compartment, ER-derived preperoxisomal vesicles carrying different membrane proteins fuse, allowing the assembly of the peroxisomal translocon. To complete formation, peroxisomes import their soluble proteins directly from the cytosol using the newly assembled translocon. Together with the ER-derived biogenic route, peroxisomal fission and segregation subsequently maintain the cellular peroxisome population. In this review we highlight the latest insights on the life cycle of peroxisomes and show how the new cell biology concept of peroxisome formation affects our thinking about peroxisome-related diseases and their evolutionary past. The future challenge lies in the identification of all the proteins involved in this elaborate biogenic process and the dissection of their mechanism of action.
Topics: Animals; Endoplasmic Reticulum; Humans; Membrane Proteins; Peroxisomes; Protein Transport
PubMed: 23414306
DOI: 10.1146/annurev-biochem-081111-125123 -
Current Opinion in Cell Biology Dec 2004The accumulation of misfolded proteins (e.g. mutant or damaged proteins) triggers cellular stress responses that protect cells against the toxic buildup of such... (Review)
Review
The accumulation of misfolded proteins (e.g. mutant or damaged proteins) triggers cellular stress responses that protect cells against the toxic buildup of such proteins. However, prolonged stress due to the buildup of these toxic proteins induces specific death pathways. Dissecting these pathways should be valuable in understanding the pathogenesis of, and ultimately in designing therapy for, neurodegenerative diseases that feature misfolded proteins.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Humans; Models, Biological; Molecular Chaperones; Neurodegenerative Diseases; Oxidative Stress; Protein Denaturation; Protein Folding; Proteins; Signal Transduction
PubMed: 15530777
DOI: 10.1016/j.ceb.2004.09.012 -
Advances in Experimental Medicine and... 2007The endoplasmic reticulum is the site of entry into the secretory pathway and represents a major and particularly crowded site of protein biosynthesis. In addition to... (Review)
Review
The endoplasmic reticulum is the site of entry into the secretory pathway and represents a major and particularly crowded site of protein biosynthesis. In addition to the complexity of protein folding in any organelle, the ER environment poses further dangers and constraints to the process. A quality control apparatus exists to monitor the maturation of proteins in the ER. Nascent polypeptide chains are specifically prevented from traveling further along the secretory pathway until they have completed their folding or assembly. Proteins that cannot achieve a proper conformation are recognized and removed from the ER for degradation by the 26S proteasome. Finally, the homeostasis of the ER is vigilantly monitored and changes that impinge upon the proper maturation of proteins in this organelle lead to the activation of a signal transduction cascade that serves to restore balance to the ER. Recent studies suggest that some of these diverse functions may be achieved due to the organization of the ER into functional and perhaps even physical sub-domains.
Topics: Animals; Calnexin; Endoplasmic Reticulum; Humans; Molecular Chaperones; Multiprotein Complexes; Protein Biosynthesis; Protein Folding
PubMed: 17205673
DOI: 10.1007/978-0-387-39975-1_4 -
Traffic (Copenhagen, Denmark) Sep 2008Protein quality control (QC) within the endoplasmic reticulum and the related unfolded protein response (UPR) pathway of signal transduction are major regulators of the... (Review)
Review
Protein quality control (QC) within the endoplasmic reticulum and the related unfolded protein response (UPR) pathway of signal transduction are major regulators of the secretory pathway, which is involved in virtually any aspect of development and reproduction. The study of plant-specific processes such as pathogen response, seed development and the synthesis of seed storage proteins and of particular toxins is providing novel insights, with potential implications for the general recognition events and mechanisms of action of QC and UPR.
Topics: Endoplasmic Reticulum; Plant Physiological Phenomena; Plant Proteins; Protein Folding; Secretory Pathway; Signal Transduction; Stress, Physiological
PubMed: 18557840
DOI: 10.1111/j.1600-0854.2008.00780.x -
Cell Calcium 2002In the complex signalling interplay that allows extracellular signals to be decoded into activation of apoptotic cell death, Ca(2+) plays a significant role. This is... (Review)
Review
In the complex signalling interplay that allows extracellular signals to be decoded into activation of apoptotic cell death, Ca(2+) plays a significant role. This is supported not only by evidence linking alterations in Ca(2+) homeostasis to the triggering of apoptotic (and in some cases necrotic) cell death, but also by recent data indicating that a key anti-apoptotic protein, Bcl-2, has a direct effect on ER Ca(2+) handling. We will briefly summarise the first aspect, and describe in more detail these new data, demonstrating that (i) Bcl-2 reduces the state of filling of the ER Ca(2+) store and (ii) this Ca(2+) signalling alteration renders the cells less sensitive to apoptotic stimuli. Overall, these results suggest that calcium homeostasis may represent a pharmacological target in the fundamental pathological process of apoptosis.
Topics: Animals; Apoptosis; Calcium; Endoplasmic Reticulum; Humans; Proto-Oncogene Proteins c-bcl-2
PubMed: 12543100
DOI: 10.1016/s0143416002002014 -
Nature Reviews. Molecular Cell Biology Jan 2004Although the interphase nuclear envelope is continuous with the endoplasmic reticulum, it is distinct from the endoplasmic reticulum in both form and composition. In... (Review)
Review
Although the interphase nuclear envelope is continuous with the endoplasmic reticulum, it is distinct from the endoplasmic reticulum in both form and composition. In metazoans, the nuclear envelope breaks down during mitosis and is thought to be completely reabsorbed by the endoplasmic reticulum. How these near neighbours are sorted out at the end of mitosis is an interesting mystery.
Topics: Animals; Endoplasmic Reticulum; Interphase; Mitosis; Nuclear Envelope
PubMed: 14663490
DOI: 10.1038/nrm1263 -
European Journal of Pharmacology Dec 2009The endoplasmic reticulum (ER) is the site of synthesis and folding of secretory and membrane bound proteins. The capacity of the ER to process proteins is limited and... (Review)
Review
The endoplasmic reticulum (ER) is the site of synthesis and folding of secretory and membrane bound proteins. The capacity of the ER to process proteins is limited and the accumulation of unfolded and misfolded proteins can lead to ER stress which has been associated with a wide range of diseases including cancer. In this review we initially provide an overview of our current understanding of how cells respond to ER stress at the molecular level and the key players involved in mediating the unfolded protein response (UPR). We review the evidence suggesting that the ER stress response could be important for the growth and development of tumors under stressful growth conditions such as hypoxia or glucose deprivation, which are commonly encountered by most solid tumors, and we analyse how it may be possible to exploit the unfolded protein response as an anticancer strategy. Two approaches to target the unfolded protein response are proposed-the first involves inhibiting components of the unfolded protein response so cells cannot adapt to stressful conditions and the second involves overloading the unfolded protein response so the cell is unable to cope, leading to cell death. We focused on proteins with an enzymatic activity that can be targeted by small molecule inhibitors as this is one of the most common approaches utilized by drug discovery companies. Finally, we review drugs currently in clinical development that affect the ER stress response and that may have potential as anti-tumor agents alone or in combination with other chemotherapeutics.
Topics: Animals; Antineoplastic Agents; Cell Death; Disease Progression; Drug Delivery Systems; Drug Design; Endoplasmic Reticulum; Humans; Neoplasms; Protein Folding; Proteins
PubMed: 19835867
DOI: 10.1016/j.ejphar.2009.06.064