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Current Biology : CB Dec 2022Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo... (Review)
Review
Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo material. This is achieved by the sequestration of the cargo within double-membrane vesicles termed autophagosomes, which form de novo around the cargo and subsequently deliver their content to lysosomes for degradation. The importance of selective autophagy is exemplified by the various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. It has become evident that cargo receptors are acting as Swiss army knives in selective autophagy by recognizing the cargo, orchestrating the recruitment of the machinery for autophagosome biogenesis, and closely aligning the membrane with the cargo. Furthermore, cargo receptors sequester ubiquitinated proteins into larger condensates upstream of autophagy induction. Here, we review recent insights into the mechanisms of action of cargo receptors in selective autophagy by focusing on the roles of sequestosome-like cargo receptors in the degradation of misfolded, ubiquitinated proteins and damaged mitochondria. We also highlight at which steps defects in their function result in the accumulation of harmful material and how this knowledge may guide the design of future therapies.
Topics: Ubiquitinated Proteins; Macroautophagy; Autophagy; Autophagosomes; Carrier Proteins
PubMed: 36538890
DOI: 10.1016/j.cub.2022.11.002 -
Biochimica Et Biophysica Acta.... Jan 2020The origin of the autophagosomal membrane started to be debated by scientists working in the field within one year of the modern definition of autophagy in 1963. There... (Review)
Review
The origin of the autophagosomal membrane started to be debated by scientists working in the field within one year of the modern definition of autophagy in 1963. There is now converging evidence from older and newer studies that the endoplasmic reticulum is involved in formation of autophagosomes. Thus, it is possible to trace from early morphological work - done without the benefit of molecular descriptions - to recent studies - dissecting how specific proteins nucleate autophagosome biogenesis - a long series of experimental findings that are beginning to answer the 55-year old question with some confidence. The view that has emerged is that specialised regions of the endoplasmic reticulum, in dynamic cross talk with most intracellular organelles via membrane contact sites, provide a platform for autophagosome biogenesis.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Endoplasmic Reticulum; Humans; Membrane Proteins
PubMed: 30890442
DOI: 10.1016/j.bbalip.2019.03.005 -
Cold Spring Harbor Perspectives in... Nov 2022Autophagy is an intracellular degradation system involving de novo generation of autophagosomes, which function as a transporting vesicle of cytoplasmic components to... (Review)
Review
Autophagy is an intracellular degradation system involving de novo generation of autophagosomes, which function as a transporting vesicle of cytoplasmic components to lysosomes for degradation. Isolation membranes (IMs) or phagophores, the precursor membranes of autophagosomes, require millions of phospholipids to expand and transform into autophagosomes, with the endoplasmic reticulum (ER) being the primary lipid source. Recent advances in structural and biochemical studies of autophagy-related proteins have revealed their lipid transport activities: Atg2 at the interface between IM and ER possesses intermembrane lipid transfer activities, while Atg9 at IM and VMP1 and TMEM41B at ER possess lipid scrambling activities. In this review, we summarize recent advances in the establishment of the lipid transport activities of these proteins and their collaboration mechanisms for lipid transport between the ER and IM, and further discuss how unidirectional lipid transport from the ER to IM occurs during autophagosome formation.
Topics: Membrane Proteins; Endoplasmic Reticulum; Autophagosomes; Autophagy; Lipids
PubMed: 35940912
DOI: 10.1101/cshperspect.a041254 -
Plant Physiology Jan 2018Environmental stress activates autophagy and leads to autophagosome formation at the endoplasmic reticulum. (Review)
Review
Environmental stress activates autophagy and leads to autophagosome formation at the endoplasmic reticulum.
Topics: Autophagosomes; Autophagy; Cell Membrane; Models, Biological
PubMed: 29061903
DOI: 10.1104/pp.17.01236 -
Journal of Molecular Biology May 2016Macroautophagy is an evolutionarily conserved dynamic pathway that functions primarily in a degradative manner. A basal level of macroautophagy occurs constitutively,... (Review)
Review
Macroautophagy is an evolutionarily conserved dynamic pathway that functions primarily in a degradative manner. A basal level of macroautophagy occurs constitutively, but this process can be further induced in response to various types of stress including starvation, hypoxia and hormonal stimuli. The general principle behind macroautophagy is that cytoplasmic contents can be sequestered within a transient double-membrane organelle, an autophagosome, which subsequently fuses with a lysosome or vacuole (in mammals, or yeast and plants, respectively), allowing for degradation of the cargo followed by recycling of the resulting macromolecules. Through this basic mechanism, macroautophagy has a critical role in cellular homeostasis; however, either insufficient or excessive macroautophagy can seriously compromise cell physiology, and thus, it needs to be properly regulated. In fact, a wide range of diseases are associated with dysregulation of macroautophagy. There has been substantial progress in understanding the regulation and molecular mechanisms of macroautophagy in different organisms; however, many questions concerning some of the most fundamental aspects of macroautophagy remain unresolved. In this review, we summarize current knowledge about macroautophagy mainly in yeast, including the mechanism of autophagosome biogenesis, the function of the core macroautophagic machinery, the regulation of macroautophagy and the process of cargo recognition in selective macroautophagy, with the goal of providing insights into some of the key unanswered questions in this field.
Topics: Autophagosomes; Autophagy; Organelle Biogenesis; Saccharomyces cerevisiae
PubMed: 26908221
DOI: 10.1016/j.jmb.2016.02.021 -
Prostaglandins & Other Lipid Mediators Jan 2016Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and... (Review)
Review
Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Δ(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes.
Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Cannabinoids; Cannabis; Humans; Models, Biological; Neoplasms; Receptors, Cannabinoid
PubMed: 26732541
DOI: 10.1016/j.prostaglandins.2015.12.006 -
Cell Biology and Toxicology Apr 2017Autophagy is a lysosomal degradation pathway of eukaryotic cells that is highly conserved from yeast to mammals. During this process, cooperating protein complexes are... (Review)
Review
Autophagy is a lysosomal degradation pathway of eukaryotic cells that is highly conserved from yeast to mammals. During this process, cooperating protein complexes are recruited in a hierarchic order to the phagophore assembly site (PAS) to mediate the elongation and closure of double-membrane vesicles called autophagosomes, which sequester cytosolic components and deliver their content to the endolysosomal system for degradation. As a major cytoprotective mechanism, autophagy plays a key role in the stress response against nutrient starvation, hypoxia, and infections. Although numerous studies reported that impaired function of core autophagy proteins also contributes to the development and progression of various human diseases such as neurodegenerative disorders, cardiovascular and muscle diseases, infections, and different types of cancer, the function of this process in human diseases remains unclear. Evidence often suggests a controversial role for autophagy in the pathomechanisms of these severe disorders. Here, we provide an overview of the molecular mechanisms of autophagy and summarize the recent advances on its function in human health and disease.
Topics: Animals; Autophagosomes; Autophagy; Disease; Humans; Models, Biological; Translational Research, Biomedical
PubMed: 27957648
DOI: 10.1007/s10565-016-9374-5 -
Journal of Molecular Biology Jan 2020Eukaryotic cells have the capacity to degrade intracellular components through a lysosomal degradation pathway called macroautophagy (henceforth referred to as... (Review)
Review
Eukaryotic cells have the capacity to degrade intracellular components through a lysosomal degradation pathway called macroautophagy (henceforth referred to as autophagy) in which superfluous or damaged cytosolic entities are engulfed and separated from the rest of the cell constituents into double membraned vesicles known as autophagosomes. Autophagosomes then fuse with endosomes and lysosomes, where cargo is broken down into basic building blocks that are released to the cytoplasm for the cell to reuse. Autophagic degradation can target either cytoplasmic material in bulk (non-selective autophagy) or particular cargo in what is called selective autophagy. Proper autophagic turnover requires the orchestrated participation of several players that need to be tightly and temporally coordinated. Whereas a large number of autophagy-related (ATG) proteins have been identified and their functions and regulation are starting to be understood, there is substantially less knowledge regarding the specific lipids constituting the autophagic membranes as well as their role in initiating, enabling or regulating the autophagic process. This review focuses on lipids and their corresponding binding proteins that are crucial in the process of selective autophagy.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Humans; Lipid Metabolism; Macroautophagy; Mitophagy; Protein Binding
PubMed: 31202884
DOI: 10.1016/j.jmb.2019.05.051 -
Molecular Cell Apr 2022As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and... (Review)
Review
As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and cellular homeostasis. This evolutionarily conserved pathway singles out intracellular substrates for elimination via encapsulation within a double-membrane vesicle and delivery to the lysosome for degradation. Multiple cancers disrupt normal regulation of autophagy and hijack its degradative ability to remodel their proteome, reprogram their metabolism, and adapt to environmental challenges, making the autophagy-lysosome system a prime target for anti-cancer interventions. Here, we discuss the roles of autophagy in tumor progression, including cancer-specific mechanisms of autophagy regulation and the contribution of tumor and host autophagy in metabolic regulation, immune evasion, and malignancy. We further discuss emerging proteomics-based approaches for systematic profiling of autophagosome-lysosome composition and contents. Together, these approaches are uncovering new features and functions of autophagy, leading to more effective strategies for targeting this pathway in cancer.
Topics: Autophagosomes; Autophagy; Humans; Lysosomes; Neoplasms; Quality Control
PubMed: 35452618
DOI: 10.1016/j.molcel.2022.03.023 -
Autophagy Jul 2023Autophagosome isolation enables the thorough investigation of structural components and engulfed materials. Recently, we introduced a novel antibody-based FACS-mediated...
Autophagosome isolation enables the thorough investigation of structural components and engulfed materials. Recently, we introduced a novel antibody-based FACS-mediated method for isolation of native macroautophagic/autophagic vesicles and confirmed the quality of the preparations. We performed phospholipidomic and proteomic analyses to characterize autophagic vesicle-associated phospholipids and protein cargoes under different autophagy conditions. Lipidomic analyses identified phosphoglycerides and sphingomyelins within autophagic vesicles and revealed that the lipid composition was unaffected by different rates of autophagosome formation. Proteomic analyses identified more than 4500 potential autophagy substrates and showed that in comparison to autophagic vesicles isolated under basal autophagy conditions, starvation only marginally affected the cargo profile. Proteasome inhibition, however, resulted in the enhanced degradation of ubiquitin-proteasome system components. Taken together, the novel isolation method enriched large quantities of autophagic vesicles and enabled detailed analyses of their lipid and cargo composition.
Topics: Autophagy; Proteasome Endopeptidase Complex; Proteomics; Autophagosomes; Lipids
PubMed: 36416088
DOI: 10.1080/15548627.2022.2151188