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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 -
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 -
Cell Research Jan 2014Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and... (Review)
Review
Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.
Topics: Animals; Autophagy; Homeostasis; Humans; Lysosomes; Phagosomes; Pichia; Protein Serine-Threonine Kinases; Saccharomyces cerevisiae; Vacuoles
PubMed: 24366339
DOI: 10.1038/cr.2013.168 -
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 -
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 -
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 -
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 -
Autophagy Oct 2021Macroautophagy/autophagy refers to the engulfment of cellular contents selected for lysosomal degradation. The final step in autophagy is the fusion of autophagosome... (Review)
Review
Macroautophagy/autophagy refers to the engulfment of cellular contents selected for lysosomal degradation. The final step in autophagy is the fusion of autophagosome with the lysosome, which is mediated by SNARE proteins. Of the SNAREs, autophagosome-localized Q-SNAREs, such as STX17 and SNAP29, and lysosome-localized R-SNAREs, such as VAMP8 or VAMP7, have been reported to be involved. Recent studies also reveal participation of the R-SNARE, YKT6, in autophagosome-lysosome fusion. These SNAREs, with the help of other regulatory factors, act coordinately to spatiotemporally control the fusion process. Besides regulating autophagosome-lysosome fusion, some SNAREs, such as STX17, also function in other autophagic processes, including autophagosome formation and mitophagy. A better understanding of the functions of SNAREs will shed light on the molecular mechanisms of autophagosome-lysosome fusion as well as on the mechanisms by which autophagy is globally regulated.: ATG: autophagy related; DNM1L: dynamin 1 like; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; IRGM: immunity related GTPase M; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PLEKHM1: pleckstrin homology and RUN domain containing M1; PRKN: PRKN RBR E3 ubiquitin protein ligase; RAB2A: RAB2A, member RAS oncogene family; RAB33B: RAB33B, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; RB1CC1: RB1 inducible coiled-coil 1; RTN3: reticulon 3; RUBCNL: rubicon like autophagy enhancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP29: synaptosomal associated protein 29; STX17: syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1; VAMP7: vesicle associated membrane protein 7; VAMP8: vesicle associated membrane protein 8; YKT6: YKT6 v-SNARE homolog.
Topics: Autophagosomes; Autophagy; Lysosomes; Macroautophagy; Membrane Fusion; Qa-SNARE Proteins; R-SNARE Proteins; SNARE Proteins
PubMed: 32924745
DOI: 10.1080/15548627.2020.1823124 -
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 -
Autophagy Dec 2021The gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated... (Review)
Review
The gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders. ATG/Atg: autophagy related; BPAN: ß-propeller protein associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; EEG: electroencephalograph; ENO2/neuron-specific enolase, enolase 2; EOEE: early-onset epileptic encephalopathy; ER: endoplasmic reticulum; ID: intellectual disability; IDR: intrinsically disordered region; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NCOA4: nuclear receptor coactivator 4; PtdIns3P: phosphatidylinositol-3-phosphate; RLS: Rett-like syndrome; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.
Topics: Autophagy; Carrier Proteins; Humans; Macroautophagy; Neurodegenerative Diseases; Neurodevelopmental Disorders
PubMed: 33843443
DOI: 10.1080/15548627.2021.1899669