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Cell Discovery 2020Autophagy is a major intracellular degradation system that derives its degradative abilities from the lysosome. The most well-studied form of autophagy is... (Review)
Review
Autophagy is a major intracellular degradation system that derives its degradative abilities from the lysosome. The most well-studied form of autophagy is macroautophagy, which delivers cytoplasmic material to lysosomes via the double-membraned autophagosome. Other forms of autophagy, namely chaperone-mediated autophagy and microautophagy, occur directly on the lysosome. Besides providing the means for degradation, lysosomes are also involved in autophagy regulation and can become substrates of autophagy when damaged. During autophagy, they exhibit notable changes, including increased acidification, enhanced enzymatic activity, and perinuclear localization. Despite their importance to autophagy, details on autophagy-specific regulation of lysosomes remain relatively scarce. This review aims to provide a summary of current understanding on the behaviour of lysosomes during autophagy and outline unexplored areas of autophagy-specific lysosome research.
PubMed: 32047650
DOI: 10.1038/s41421-020-0141-7 -
Molecular Cell Nov 2021The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here...
The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8 T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.
Topics: Adult; Aged; Aged, 80 and over; Animals; Autophagy; CD8-Positive T-Lymphocytes; Carcinogenesis; Cell Transformation, Neoplastic; Colorectal Neoplasms; Cycloheximide; Female; HEK293 Cells; Humans; Immunophenotyping; Interferon Regulatory Factor-3; Interferons; Isoenzymes; Male; Membrane Proteins; Mice; Middle Aged; Neoplasm Transplantation; Phosphorylation; Prognosis; Protein Kinase C; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factors; Up-Regulation
PubMed: 34560002
DOI: 10.1016/j.molcel.2021.08.039 -
Antioxidants & Redox Signaling Mar 2023Autophagy is critical to cellular homeostasis. Emergence of the concept of regulated necrosis, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial... (Review)
Review
Autophagy is critical to cellular homeostasis. Emergence of the concept of regulated necrosis, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial membrane-permeability transition (MPT)-derived necrosis, has revolutionized the research into necrosis. Both altered autophagy and regulated necrosis contribute to major human diseases. Recent studies reveal an intricate interplay between autophagy and regulated necrosis. Understanding the interplay at the molecular level will provide new insights into the pathophysiology of related diseases. Among the three forms of autophagy, macroautophagy is better studied for its crosstalk with regulated necrosis. Macroautophagy seemingly can either antagonize or promote regulated necrosis, depending upon the form of regulated necrosis, the type of cells or stimuli, and other cellular contexts. This review will critically analyze recent advances in the molecular mechanisms governing the intricate dialogues between macroautophagy and main forms of regulated necrosis. The dual roles of autophagy, either pro-survival or pro-death characteristics, intricate the mechanistic relationship between autophagy and regulated necrosis at molecular level in various pathological conditions. Meanwhile, key components of regulated necrosis are also involved in the regulation of autophagy, which further complicates the interrelationship. Resolving the controversies over causation between altered autophagy and a specific form of regulated necrosis requires approaches that are more definitive, where rigorous evaluation of autophagic flux and the development of more reliable and specific methods to quantify each form of necrosis will be essential. The relationship between chaperone-mediated autophagy or microautophagy and regulated necrosis remains largely unstudied. 38, 550-580.
Topics: Humans; Apoptosis; Necrosis; Pyroptosis; Ferroptosis; Autophagy
PubMed: 36053716
DOI: 10.1089/ars.2022.0110 -
Neuroscience Bulletin Aug 2015Chaperone-mediated autophagy (CMA), one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the... (Review)
Review
Chaperone-mediated autophagy (CMA), one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif biochemically related to the pentapeptide KFERQ. Along with the other two lysosomal pathways, macro- and micro-autophagy, CMA is essential for maintaining cellular homeostasis and survival by selectively degrading misfolded, oxidized, or damaged cytosolic proteins. CMA plays an important role in pathologies such as cancer, kidney disorders, and neurodegenerative diseases. Neurons are post-mitotic and highly susceptible to dysfunction of cellular quality-control systems. Maintaining a balance between protein synthesis and degradation is critical for neuronal functions and homeostasis. Recent studies have revealed several new mechanisms by which CMA protects neurons through regulating factors critical for their viability and homeostasis. In the current review, we summarize recent advances in the understanding of the regulation and physiology of CMA with a specific focus on its possible roles in neuroprotection.
Topics: Alzheimer Disease; Animals; Autophagy; Humans; Huntington Disease; Lysosomes; Molecular Chaperones; Neurons; Parkinson Disease
PubMed: 26206599
DOI: 10.1007/s12264-015-1540-x -
International Journal of Molecular... Oct 2023Autophagy is a lysosomal degradation process known as autophagic flux, involving the engulfment of damaged proteins and organelles by double-membrane autophagosomes. It... (Review)
Review
Autophagy is a lysosomal degradation process known as autophagic flux, involving the engulfment of damaged proteins and organelles by double-membrane autophagosomes. It comprises microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. Macroautophagy consists of three stages: induction, autophagosome formation, and autolysosome formation. Atg8-family proteins are valuable for tracking autophagic structures and have been widely utilized for monitoring autophagy. The conversion of LC3 to its lipidated form, LC3-II, served as an indicator of autophagy. Autophagy is implicated in human pathophysiology, such as neurodegeneration, cancer, and immune disorders. Moreover, autophagy impacts urological diseases, such as interstitial cystitis /bladder pain syndrome (IC/BPS), ketamine-induced ulcerative cystitis (KIC), chemotherapy-induced cystitis (CIC), radiation cystitis (RC), erectile dysfunction (ED), bladder outlet obstruction (BOO), prostate cancer, bladder cancer, renal cancer, testicular cancer, and penile cancer. Autophagy plays a dual role in the management of urologic diseases, and the identification of potential biomarkers associated with autophagy is a crucial step towards a deeper understanding of its role in these diseases. Methods for monitoring autophagy include TEM, Western blot, immunofluorescence, flow cytometry, and genetic tools. Autophagosome and autolysosome structures are discerned via TEM. Western blot, immunofluorescence, northern blot, and RT-PCR assess protein/mRNA levels. Luciferase assay tracks flux; GFP-LC3 transgenic mice aid study. Knockdown methods (miRNA and RNAi) offer insights. This article extensively examines autophagy's molecular mechanism, pharmacological regulation, and therapeutic application involvement in urological diseases.
Topics: Animals; Male; Mice; Humans; Testicular Neoplasms; Autophagy; Autophagosomes; Autophagy-Related Protein 8 Family; Mice, Transgenic; Cystitis; Microtubule-Associated Proteins; Lysosomes
PubMed: 37834333
DOI: 10.3390/ijms241914887 -
Current Medicinal Chemistry 2019Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include... (Review)
Review
Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation. Autophagy pathways include macroautophagy, chaperone-mediated autophagy and microautophagy, each involving different mechanisms of substrate delivery to lysosome. Defects of these pathways and the resulting accumulation of protein aggregates represent a common pathobiological feature of neurodegenerative disorders such as Alzheimer, Parkinson and Huntington disease. This review provides an overview of the role of autophagy in Parkinson's disease (PD) by summarizing the most relevant genetic and experimental evidence showing how this process can contribute to disease pathogenesis. Given lysosomes take part in the final step of the autophagic process, the role of lysosomal defects in the impairment of autophagy and their impact on disease will also be discussed. A glance on the role of non-neuronal autophagy in the pathogenesis of PD will be included. Moreover, we will examine novel pharmacological targets and therapeutic strategies that, by boosting autophagy, may be theoretically beneficial for PD. Special attention will be focused on natural products, such as phenolic compounds, that are receiving increasing consideration due to their potential efficacy associated with low toxicity. Although many efforts have been made to elucidate autophagic process, the development of new therapeutic interventions requires a deeper understanding of the mechanisms that may lead to autophagy defects in PD and should take into account the multifactorial nature of the disease as well as the phenotypic heterogeneity of PD patients.
Topics: Animals; Autophagy; Humans; Parkinson Disease; Phenotype
PubMed: 29484979
DOI: 10.2174/0929867325666180226094351 -
EMBO Reports Dec 2023Lysosomes are degradative organelles and signaling hubs that maintain cell and tissue homeostasis, and lysosomal dysfunction is implicated in aging and reduced...
Lysosomes are degradative organelles and signaling hubs that maintain cell and tissue homeostasis, and lysosomal dysfunction is implicated in aging and reduced longevity. Lysosomes are frequently damaged, but their repair mechanisms remain unclear. Here, we demonstrate that damaged lysosomal membranes are repaired by microautophagy (a process termed "microlysophagy") and identify key regulators of the first and last steps. We reveal the AGC kinase STK38 as a novel microlysophagy regulator. Through phosphorylation of the scaffold protein DOK1, STK38 is specifically required for the lysosomal recruitment of the AAA+ ATPase VPS4, which terminates microlysophagy by promoting the disassembly of ESCRT components. By contrast, microlysophagy initiation involves non-canonical lipidation of ATG8s, especially the GABARAP subfamily, which is required for ESCRT assembly through interaction with ALIX. Depletion of STK38 and GABARAPs accelerates DNA damage-induced cellular senescence in human cells and curtails lifespan in C. elegans, respectively. Thus, microlysophagy is regulated by STK38 and GABARAPs and could be essential for maintaining lysosomal integrity and preventing aging.
Topics: Animals; Humans; Microautophagy; Caenorhabditis elegans; Lysosomes; Intracellular Membranes; Endosomal Sorting Complexes Required for Transport; Autophagy; Microtubule-Associated Proteins; Apoptosis Regulatory Proteins; Protein Serine-Threonine Kinases
PubMed: 37987447
DOI: 10.15252/embr.202357300 -
Advances in Experimental Medicine and... 2019Autophagy plays an important role in the renewal of cellular components, which function in energy production, metabolism, and clearance of damaged organelles. Both... (Review)
Review
Autophagy plays an important role in the renewal of cellular components, which function in energy production, metabolism, and clearance of damaged organelles. Both macroautophagy and microautophagy are involved in these processes. Although it was thought that nonselective macroautophagy is responsible for the clearance of damaged or old organelles, recent studies show that the clearance of cellular organelles depends on selective processes. Mitophagy is a process for selective degradation of mitochondria, which is well documented. The selective autophagy for other organelles includes endoplasmic reticulum autophagy (reticulophagy) and peroxisome autophagy (pexophagy). Autophagy is a routine pathway for cells to degrade unused proteins and damaged organelles in cells. Autophagy selectively removes dysfunctional cellular components but not damages the normally functioning organelles, to maintain the homeostasis of cells. In addition to the maintenance of the homeostasis of cells, autophagy clears the damaged organelles in disease or injury conditions to achieve cellular quality control. In some differentiated cells, such as red blood cells, some organelles are removed during the maturation, including mitochondria. The autophagy system can selectively clear the mitochondria and other organelles, which lead to the maturation of red blood cells. Dysfunction of autophagy impairs the clearance of damaged organelles, which results in injury of cells. In the maturation of red blood cells, failure to clear the cellular organelles by autophagy will disturb the normal differentiation of red blood cells, leading to a series of diseases such as anemia.
Topics: Autophagy; Homeostasis; Humans; Mitochondria; Mitophagy; Organelles
PubMed: 31776996
DOI: 10.1007/978-981-15-0602-4_19 -
Trends in Cell Biology Dec 2023Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There are three types of autophagy, i.e.,... (Review)
Review
Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There are three types of autophagy, i.e., macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. In macroautophagy, a portion of the cytoplasm is wrapped by the autophagosome, which then fuses with lysosomes and delivers the engulfed cytoplasm for degradation. In CMA, the translocation of cytosolic substrates to the lysosomal lumen is directly across the limiting membrane of lysosomes. In microautophagy, lytic organelles, including endosomes or lysosomes, take up a portion of the cytoplasm directly. Although macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become evident that microautophagy plays a variety of cellular roles from yeast to mammals. Here we review the very recent updates of microautophagy. In particular, we focus on the feature of the degradative substrates and the molecular machinery that mediates microautophagy.
PubMed: 38104013
DOI: 10.1016/j.tcb.2023.11.005 -
Autophagy Mar 2021Nucleophagy, the mechanism for autophagic degradation of nuclear material, occurs in both a macro- and micronucleophagic manner. Upon nitrogen deprivation, we observed,...
Nucleophagy, the mechanism for autophagic degradation of nuclear material, occurs in both a macro- and micronucleophagic manner. Upon nitrogen deprivation, we observed, in an in-depth fluorescence microscopy study, the formation of micronuclei: small parts of superfluous nuclear components surrounded by perinuclear ER. We identified two types of micronuclei associated with a corresponding autophagic mode. Our results showed that macronucleophagy degraded these smaller micronuclei. Engulfed in Atg8-positive phagophores and containing cargo receptor Atg39, macronucleophagic structures revealed finger-like extensions when observed in 3-dimensional reconstitutions of fluorescence microscopy images, suggesting directional growth. Interestingly, in the late stages of phagophore elongation, the adjacent vacuolar membrane showed a reduction of integral membrane protein Pho8. This change in membrane composition could indicate the formation of a specialized vacuolar domain, required for autophagosomal fusion. Significantly larger micronuclei formed at nucleus vacuole junctions and were identified as a substrate of piecemeal microautophagy of the nucleus (PMN), by the presence of the integral membrane protein Nvj1. Micronuclei sequestered by vacuolar invaginations also contained Atg39. A detailed investigation revealed that both Atg39 and Atg8 accumulated between the vacuolar tips. These findings suggest a role for Atg39 in micronucleophagy. Indeed, following the degradation of Nvj1, an exclusive substrate of PMN, in immunoblots, we could confirm the essential role of Atg39 for PMN. Our study thus details the involvement of Atg8 in both macronucleophagy and PMN and identifies Atg39 as the general cargo receptor for nucleophagic processes. DIC: Differential interference contrast, FWHM: Full width at half maximum, IQR: Interquartile range, MIPA: Micropexophagy-specific membrane apparatus, NLS: Nuclear localization signal, NVJ: Nucleus vacuole junction, PMN: Piecemeal microautophagy of the nucleus, pnER: Perinuclear ER.
Topics: Autophagy; Carrier Proteins; Cell Nucleus; Endoplasmic Reticulum; Membrane Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Vesicular Transport Proteins
PubMed: 32046569
DOI: 10.1080/15548627.2020.1725402