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Nature Reviews. Molecular Cell Biology Aug 2020Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human... (Review)
Review
Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.
Topics: Animals; Apoptosis; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Neoplasms; Protein Folding; Proteins; Signal Transduction; Unfolded Protein Response
PubMed: 32457508
DOI: 10.1038/s41580-020-0250-z -
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 -
Physiological Reviews Jul 2022ER-phagy (reticulophagy) defines the degradation of portions of the endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part of the self-digestion (i.e.,... (Review)
Review
ER-phagy (reticulophagy) defines the degradation of portions of the endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part of the self-digestion (i.e., autophagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance of ER subdomains participates in the control of ER size and activity during ER stress, the reestablishment of ER homeostasis after ER stress resolution, and the removal of ER parts in which aberrant and potentially cytotoxic material has been segregated. ER-phagy relies on the individual and/or concerted activation of the ER-phagy receptors, ER peripheral or integral membrane proteins that share the presence of LC3/Atg8-binding motifs in their cytosolic domains. ER-phagy involves the physical separation of portions of the ER from the bulk ER network and their delivery to the endolysosomal/vacuolar catabolic district. This last step is accomplished by a variety of mechanisms including macro-ER-phagy (in which ER fragments are sequestered by double-membrane autophagosomes that eventually fuse with lysosomes/vacuoles), micro-ER-phagy (in which ER fragments are directly engulfed by endosomes/lysosomes/vacuoles), or direct fusion of ER-derived vesicles with lysosomes/vacuoles. ER-phagy is dysfunctional in specific human diseases, and its regulators are subverted by pathogens, highlighting its crucial role for cell and organism life.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Lysosomes; Membrane Proteins
PubMed: 35188422
DOI: 10.1152/physrev.00038.2021 -
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 -
Molecular Cell Apr 2022Endoplasmic reticulum quality control (ERQC) pathways comprising chaperones, folding enzymes, and degradation factors ensure the fidelity of ER protein folding and... (Review)
Review
Endoplasmic reticulum quality control (ERQC) pathways comprising chaperones, folding enzymes, and degradation factors ensure the fidelity of ER protein folding and trafficking to downstream secretory environments. However, multiple factors, including tissue-specific secretory proteomes, environmental and genetic insults, and organismal aging, challenge ERQC. Thus, a key question is: how do cells adapt ERQC to match the diverse, ever-changing demands encountered during normal physiology and in disease? The answer lies in the unfolded protein response (UPR), a signaling mechanism activated by ER stress. In mammals, the UPR comprises three signaling pathways regulated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Upon activation, these UPR pathways remodel ERQC to alleviate cellular stress and restore ER function. Here, we describe how UPR signaling pathways adapt ERQC, highlighting their importance for maintaining ER function across tissues and the potential for targeting the UPR to mitigate pathologies associated with protein misfolding diseases.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Mammals; Quality Control; Signal Transduction; Unfolded Protein Response
PubMed: 35452616
DOI: 10.1016/j.molcel.2022.03.025 -
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 Sep 2023Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a...
Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.
Topics: Endoplasmic Reticulum; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Protein Kinases; Ubiquitin-Protein Ligases; Drosophila melanogaster; Animals
PubMed: 37633267
DOI: 10.1016/j.cell.2023.08.008 -
Progress in Lipid Research Jan 2023The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid... (Review)
Review
The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Lipid Metabolism; Lipids
PubMed: 36379317
DOI: 10.1016/j.plipres.2022.101198 -
Developmental Cell Apr 2021Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression;... (Review)
Review
Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Macroautophagy; Mitophagy; Neoplasms
PubMed: 33689692
DOI: 10.1016/j.devcel.2021.02.010 -
Seminars in Cancer Biology Nov 2020Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic... (Review)
Review
Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.
Topics: Animals; Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Neoplasms; Signal Transduction; Unfolded Protein Response
PubMed: 31838023
DOI: 10.1016/j.semcancer.2019.11.007