Ubiquitination and selective autophagy
TL;DR: This review focuses on the special role of ubiquitin signals and selective autophagy receptors in sorting a variety of autophagic cargos.
Abstract: Ubiquitination has long been recognised as a key determinator of protein fate by tagging proteins for proteasomal degradation. Most recently, the ability of conjugated ubiquitin chains to confer selectivity to autophagy was demonstrated. Although autophagy was first believed to be a bulk, non-selective ‘self-eating’ degradative process, the molecular mechanisms of selectivity are now starting to emerge. With the discovery of autophagy receptors – which bind both ubiquitinated substrates and autophagy specific light chain 3 (LC3) modifier on the inner sheath of autophagosomes – a new pathway of selective autophagy is being unravelled. In this review, we focus on the special role of ubiquitin signals and selective autophagy receptors in sorting a variety of autophagic cargos.
Citations
More filters
TL;DR: The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens, and the disruption of the relationship between autphagy and apoptosis has important pathophysiological consequences.
Abstract: Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to 'autophagic cell death'. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences.
1,721 citations
TL;DR: An overview of the role of autophagy in neurodegenerative disease is provided, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease.
Abstract: This Review provides an overview of the role of autophagy, a key lysosomal degradative process, in neurodegenerative diseases. The study of various neurodegenerative diseases has shown that defects in autophagy can arise at different points in the pathway, and this has implications for the successful modulation of autophagy for therapeutic purposes. The Review also discusses the latest developments in targeting alterations in autophagy as a therapeutic strategy for neurodegenerative diseases.
1,643 citations
TL;DR: Beyond the simplistic view of a process exclusively dedicated to the turnover of cellular components, recent data have uncovered unexpected functions for autophagy and the autophagic-related genes, such as regulation of metabolism, membrane transport and modulation of host defenses — indicating the novel frontiers lying ahead.
Abstract: Autophagy maintains cell, tissue and organism homeostasis through degradation. Complex post-translational modulation of the Atg (autophagy-related) proteins adds additional entry points for crosstalk with other cellular processes and helps define cell-type-specific regulations of autophagy. Beyond the simplistic view of a process exclusively dedicated to the turnover of cellular components, recent data have uncovered unexpected functions for autophagy and the autophagy-related genes, such as regulation of metabolism, membrane transport and modulation of host defenses--indicating the novel frontiers lying ahead.
971 citations
[...]
TL;DR: In multicellular organisms, cell death is a critical and active process that maintains tissue homeostasis and eliminates potentially harmful cells.
Abstract: In multicellular organisms, cell death is a critical and active process that maintains tissue homeostasis and eliminates potentially harmful cells. There are three major types of morphologically distinct cell death: apoptosis (type I cell death), autophagic cell death (type II), and necrosis (type III). All three can be executed through distinct, and sometimes overlapping, signaling pathways that are engaged in response to specific stimuli. Apoptosis is triggered when cell-surface death receptors such as Fas are bound by their ligands (the extrinsic pathway) or when Bcl2-family proapoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both pathways converge on the activation of the caspase protease family, which is ultimately responsible for the dismantling of the cell. Autophagy defines a catabolic process in which parts of the cytosol and specific organelles are engulfed by a double-membrane structure, known as the autophagosome, and eventually degraded. Autophagy is mostly a survival mechanism; nevertheless, there are a few examples of autophagic cell death in which components of the autophagic signaling pathway actively promote cell death. Necrotic cell death is characterized by the rapid loss of plasma membrane integrity. This form of cell death can result from active signaling pathways, the best characterized of which is dependent on the activity of the protein kinase RIP3.
704 citations
Cites background from "Ubiquitination and selective autoph..."
...teins are ubiquitylated and linked to the phagophore by proteins such as p62 and neighbor of breast cancer 1 (NBR1) that bind both LC3 and ubiquitin (Shaid et al. 2013)....
[...]
TL;DR: This work mapped the critical region for senescence-induced activity and identified the transcriptional regulator responsible for this regulation, GATA4, previously known as a regulator of embryonic development, which affects senescent cells and their microenvironment and suggests the existence of an independent senescENCE regulatory network that controls the SASP.
Abstract: Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.
657 citations
References
More filters
[...]
TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
7,888 citations
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
"Ubiquitination and selective autoph..." refers background in this paper
...phagy has been linked to human pathophysiology, including cancer, neurodegeneration, immune response and ageing.(4,5)...
[...]
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
"Ubiquitination and selective autoph..." refers background in this paper
...protein aggregates, indicating that p62 is indispensable for basal autophagy.(53) By directly binding to LC3 via its LIR motif, p62 becomes a selective autophagy receptor, bringing ubiquitinated protein aggregates to the emerging autophagosome....
[...]
...By directly binding to LC3 via its LIR motif, p62 becomes a selective autophagy receptor, bringing ubiquitinated protein aggregates to the emerging autophagosome.(6,53) The importance of p62 as a selective autophagy receptor for degradation of misfolded proteins or aggregates is reflected in the development of several human bone...
[...]
...NBR1 can directly bind to p62, and together they act as cargo receptors for autophagic degradation of ubiquitinated substrates.(6,7,53)...
[...]
TL;DR: It is shown that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells and this recruitment promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondira in the pathogenesis of Parkinson's disease.
Abstract: Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.
3,413 citations
"Ubiquitination and selective autoph..." refers background in this paper
...In addition, recent studies showed that Parkin promotes selective autophagy of dysfunctional mitochondria (mitophagy, see below).(37,38) By interacting with different sets of cofactors under specific conditions it may be conceivable that CHIP, Parkin and other related E3-ligases act like...
[...]
...The E3-ligase Parkin is translocated to damaged mitochondria and mediates ubiquitination of voltage-dependent anion channel 1 (VDAC1).(37) p62 is in turn recruited...
[...]
01 Jan 2007
TL;DR: In this article, the authors showed that the polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy by using a 22-residue sequence of p62 containing an evolutionarily conserved motif.
Abstract: Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B and the related -aminobutyrate receptor-associated protein and-aminobutyrate receptor-associated-like proteins. The binding is mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif. To monitor the autophagic sequestration of p62- and LC3-positive bodies, we developed a novel pH-sensitive fluorescent tag consisting of a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive green fluorescent proteins. This approach revealed that p62- and LC3-positive bodies are degraded in autolysosomes. Strikingly, even rather large p62-positive inclusion bodies (2 m diameter) become degraded by autophagy. The specific interaction between p62 and LC3, requiring the motif we have mapped, is instrumental in mediating autophagic degradation of the p62-positive bodies. We also demonstrate that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation. In fact, p62 bodies and these structures are indistinguishable. Taken together, our results clearly suggest that p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.
3,172 citations