Selective autophagy mediated by autophagic adapter proteins
TL;DR: The mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria is reviewed and the emerging picture of selectivity affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is addressed.
Abstract: Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.
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TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.
4,529 citations
Cites background from "Selective autophagy mediated by aut..."
...Thus, it has been proposed that p62 may be an autophagy receptor for degrading ubiquitinated cargos, including ubiquitinated aggregates, damaged mitochondria, ubiquitinated midbody rings, ubiquitin-tagged peroxisomes, ubiquitinated microbes, ribosomal proteins, and virus capsid proteins (Johansen and Lamark, 2011; Weidberg et al., 2011) (Figure 3)....
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...Subsequently, p62 is incorporated into the autophagosome and then degraded (Johansen and Lamark, 2011; Weidberg et al., 2011)....
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...…mitochondria, ubiquitinated midbody rings, ubiquitin-tagged peroxisomes, ubiquitinated microbes, ribosomal proteins, and virus capsid proteins (Johansen and Lamark, 2011; Weidberg et al., 2011) (Figure 3). p62 and other adaptor proteins, such as NDP52 (Thurston et al., 2009) and optineurin…...
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...) Subsequently, p62 is incorporated into the autophagosome and then degraded (Johansen and Lamark, 2011; Weidberg et al., 2011)....
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TL;DR: In their Perspective, Hoppins and Nunnari explain that the endoplasmic reticulum is an active participant in mitochondrial division and discuss how mitochondrial dynamics and cell death are linked.
Abstract: Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson’s.
2,560 citations
TL;DR: The molecular mechanism of autophagosome formation is described with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagous membrane membrane.
Abstract: Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
2,522 citations
TL;DR: This review discusses the cellular process of autophagy (“self-eating”), which plays key roles in normal development of the immune system and adaptation to stress, as well as in a wide range of disease states.
Abstract: This review discusses the cellular process of autophagy (“self-eating”), which plays key roles in normal development of the immune system and adaptation to stress, as well as in a wide range of disease states.
2,131 citations
TL;DR: As discussed in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity.
Abstract: It is increasingly understood that autophagy is an ancient defence mechanism that has become incorporated into numerous immunological pathways. As discussed in this Review, its immunological roles include the elimination of microorganisms, the control of inflammation, the regulation of antigen presentation and lymphocyte homeostasis, and the secretion of immune mediators.
1,549 citations
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TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
6,301 citations
"Selective autophagy mediated by aut..." refers background in this paper
...Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved catabolic process that involves the sequestration and transport of organelles and macromolecules to the lysosomes for degradation.(1,2) Following lysosomal degradation, recycling occurs to replenish the cell with nutrients and building blocks for anabolic processes....
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...The process is also mobilized in the innate immune response against invading microbes.(1,4,5) Yeast genetics has been vital for the elucidation of the molecular machinery involved in autophagy processes....
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TL;DR: It is demonstrated that the rat microtubule‐associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing.
Abstract: Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.
6,244 citations
"Selective autophagy mediated by aut..." refers background in this paper
..., LC3-II) is tightly bound to the autophagosomal membranes and serves as an autophagic marker protein.(14,16,18,19) The conjugation of ATG8 to PE is essential for the hemifusion of lipid membranes and is suggested to drive the expansion of the autophagosome....
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TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.
Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.
5,831 citations
"Selective autophagy mediated by aut..." refers background in this paper
...The process is also mobilized in the innate immune response against invading microbes.(1,4,5) Yeast genetics has been vital for the elucidation of the molecular machinery involved in autophagy processes....
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TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.
Abstract: Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.
3,684 citations
TL;DR: It is demonstrated that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation and p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.
3,676 citations