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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 -
Journal of Molecular Biology Apr 2020Impaired protein homeostasis and accumulation of damaged or abnormally modified protein are common disease mechanisms in many neurodegenerative disorders, including... (Review)
Review
Impaired protein homeostasis and accumulation of damaged or abnormally modified protein are common disease mechanisms in many neurodegenerative disorders, including Parkinson's disease (PD). As one of the major degradation pathways, autophagy plays a pivotal role in maintaining effective turnover of proteins and damaged organelles in cells. Several decades of research efforts led to insights into the potential contribution of impaired autophagy machinery to α-synuclein accumulation and the degeneration of dopaminergic neurons, two major features of PD pathology. In this review, we summarize recent pathological, genetic, and mechanistic findings that link defective autophagy with PD pathogenesis in human patients, animals, and cellular models and discuss current challenges in the field.
Topics: Animals; Autophagy; Humans; Parkinson Disease
PubMed: 32061929
DOI: 10.1016/j.jmb.2020.01.037 -
Theranostics 2021Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and...
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, . In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, . Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
Topics: Autophagy; Humans; Macroautophagy; Mitophagy; Organelles
PubMed: 33391472
DOI: 10.7150/thno.49860 -
Journal of Molecular Biology Apr 2020Macroautophagy is a conserved catabolic process observed in all eukaryotic cells, during which selected cellular components are transported to and broken down within... (Review)
Review
Macroautophagy is a conserved catabolic process observed in all eukaryotic cells, during which selected cellular components are transported to and broken down within lysosomes. The process starts with the capture of unnecessary material into autophagosomes, which is followed by autophagosome-lysosome fusion to generate autolysosomes that degrade the cargo. In the past quarter-century, our knowledge about autophagosome formation almost exponentially increased, while the later steps were much less studied. This fortunately changed in the past few years, with more and more publications focusing on the fate of the completed autophagosome. In this review, we aspire to summarize the current knowledge about the molecular mechanisms of autophagosome-lysosome fusion.
Topics: Animals; Autophagosomes; Autophagy; Humans; Lysosomes; Neurodegenerative Diseases; SNARE Proteins
PubMed: 31682838
DOI: 10.1016/j.jmb.2019.10.028 -
Nature Reviews. Neuroscience Jul 2022Macroautophagy is an evolutionarily conserved process that delivers diverse cellular contents to lysosomes for degradation. As our understanding of this pathway grows,... (Review)
Review
Macroautophagy is an evolutionarily conserved process that delivers diverse cellular contents to lysosomes for degradation. As our understanding of this pathway grows, so does our appreciation for its importance in disorders of the CNS. Once implicated primarily in neurodegenerative events owing to acute injury and ageing, macroautophagy is now also linked to disorders of neurodevelopment, indicating that it is essential for both the formation and maintenance of a healthy CNS. In parallel to understanding the significance of macroautophagy across contexts, we have gained a greater mechanistic insight into its physiological regulation and the breadth of cargoes it can degrade. Macroautophagy is a broadly used homeostatic process, giving rise to questions surrounding how defects in this single pathway could cause diseases with distinct clinical and pathological signatures. To address this complexity, we herein review macroautophagy in the mammalian CNS by examining three key features of the process and its relationship to disease: how it functions at a basal level in the discrete cell types of the brain and spinal cord; which cargoes are being degraded in physiological and pathological settings; and how the different stages of the macroautophagy pathway intersect with diseases of neurodevelopment and adult-onset neurodegeneration.
Topics: Animals; Central Nervous System Diseases; Macroautophagy; Mammals
PubMed: 35505254
DOI: 10.1038/s41583-022-00588-3 -
Cell Apr 2022Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been...
Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.
Topics: Animals; Mice; Apoptosis Regulatory Proteins; Autophagy; Carrier Proteins; Chaperonin Containing TCP-1; Macroautophagy; Protein Aggregates; Sequestosome-1 Protein
PubMed: 35366418
DOI: 10.1016/j.cell.2022.03.005 -
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 -
Autophagy Jun 2020Macroautophagy/autophagy plays complex, context-dependent roles in cancer. How autophagy governs the emergence of metastatic disease has been incompletely understood. We...
Macroautophagy/autophagy plays complex, context-dependent roles in cancer. How autophagy governs the emergence of metastatic disease has been incompletely understood. We recently uncovered that genetic autophagy inhibition strongly attenuates primary tumor growth in mammary cancer models, yet paradoxically promotes spontaneous metastasis to the lung and enables the outgrowth of disseminated tumor cells (DTCs) into overt macro-metastases. Furthermore, at both primary and metastatic sites, genetic autophagy inhibition leads to the marked expansion of tumor cells exhibiting aggressive and pro-metastatic basal epithelial differentiation. These pro-metastatic effects of autophagy inhibition are due to the cytosolic accumulation of the autophagy cargo receptor NBR1 in autophagy-deficient tumor cells.
Topics: Autophagy; Breast Neoplasms; Carrier Proteins; Humans; Intracellular Signaling Peptides and Proteins; Macroautophagy
PubMed: 32267786
DOI: 10.1080/15548627.2020.1753001 -
Neural Regeneration Research Aug 2020Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role... (Review)
Review
Appropriate autophagy has protective effects on ischemic nerve tissue, while excessive autophagy may cause cell death. The inflammatory response plays an important role in the survival of nerve cells and the recovery of neural tissue after ischemia. Many studies have found an interaction between autophagy and inflammation in the pathogenesis of ischemic stroke. This study outlines recent advances regarding the role of autophagy in the post-stroke inflammatory response as follows. (1) Autophagy inhibits inflammatory responses caused by ischemic stimulation through mTOR, the AMPK pathway, and inhibition of inflammasome activation. (2) Activation of inflammation triggers the formation of autophagosomes, and the upregulation of autophagy levels is marked by a significant increase in the autophagy-forming markers LC3-II and Beclin-1. Lipopolysaccharide stimulates microglia and inhibits ULK1 activity by direct phosphorylation of p38 MAPK, reducing the flux and autophagy level, thereby inducing inflammatory activity. (3) By blocking the activation of autophagy, the activation of inflammasomes can alleviate cerebral ischemic injury. Autophagy can also regulate the phenotypic alternation of microglia through the nuclear factor-κB pathway, which is beneficial to the recovery of neural tissue after ischemia. Studies have shown that some drugs such as resveratrol can exert neuroprotective effects by regulating the autophagy-inflammatory pathway. These studies suggest that the autophagy-inflammatory pathway may provide a new direction for the treatment of ischemic stroke.
PubMed: 31997797
DOI: 10.4103/1673-5374.274331 -
The EMBO Journal Dec 2022Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned...
Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned over by autophagy, in processes termed mitophagy and pexophagy, respectively. However, despite their close relationship, it is not known if both organelles are turned over under similar conditions, and if so, how this might be coordinated molecularly. Here, we find that multiple selective autophagy pathways are activated upon iron chelation and show that mitophagy and pexophagy occur in a BNIP3L/NIX-dependent manner. We reveal that the outer mitochondrial membrane-anchored NIX protein, previously described as a mitophagy receptor, also independently localises to peroxisomes and drives pexophagy. We show this process happens in vivo, with mouse tissue that lacks NIX having a higher peroxisomal content. We further show that pexophagy is stimulated under the same physiological conditions that activate mitophagy, including cardiomyocyte and erythrocyte differentiation. Taken together, our work uncovers a dual role for NIX, not only in mitophagy but also in pexophagy, thus illustrating the interconnection between selective autophagy pathways.
Topics: Mice; Animals; Mitophagy; Macroautophagy; Peroxisomes; Apoptosis Regulatory Proteins; Autophagy; Membrane Proteins; Mitochondrial Proteins
PubMed: 36215693
DOI: 10.15252/embj.2022111115