The Experts below are selected from a list of 10944 Experts worldwide ranked by ideXlab platform
Michael Overholtzer - One of the best experts on this subject based on the ideXlab platform.
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getting picky with the Lysosome Membrane
Autophagy, 2021Co-Authors: Chan Lee, Michael OverholtzerAbstract:Lysosomes play an essential role in quality control mechanisms by functioning as the primary digestive system in mammalian cells. However, the quality control mechanisms governing healthy Lysosomes are not fully understood. Using a method to study Lysosome Membrane turnover, we discovered that LC3-lipidation on the Lysosome limiting Membrane is involved in invagination and formation of intralumenal vesicles, an activity known as microautophagy. This activity occurs in response to metabolic stress, in the form of glucose starvation, or osmotic stress induced by treatment with lysosomotropic compounds. Cells rendered deficient in the ability to lipidate LC3 through knockout of ATG5 show reduced ability to regulate Lysosome size and degradative function in response to stress. These findings demonstrate that cells can adapt to changing metabolic conditions by turning over selective portions of the lysosomal Membrane, using a mechanism that involves Lysosome-targeted LC3 lipidation and the induction of selective microautophagy.
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selective Lysosome Membrane turnover is induced by nutrient starvation
Developmental Cell, 2020Co-Authors: Chan Lee, Michael Overholtzer, Lilian Lamech, Eleanor JohnsAbstract:Lysosome function is essential for cellular homeostasis, but quality-control mechanisms that maintain healthy Lysosomes remain poorly characterized. Here, we developed a method to measure Lysosome turnover and use this to identify a selective mechanism of Membrane degradation that involves lipidation of the autophagy protein LC3 onto lysosomal Membranes and the formation of intraluminal vesicles through microautophagy. This mechanism is induced in response to metabolic stress resulting from glucose starvation or by treatment with pharmacological agents that induce osmotic stress on Lysosomes. Cells lacking ATG5, an essential component of the LC3 lipidation machinery, show reduced ability to regulate Lysosome size and degradative capacity in response to activation of this mechanism. These findings identify a selective mechanism of Lysosome Membrane turnover that is induced by stress and uncover a function for LC3 lipidation in regulating Lysosome size and activity through microautophagy.
Maja Radulovic - One of the best experts on this subject based on the ideXlab platform.
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escrt mediated Lysosome repair precedes lysophagy and promotes cell survival
The EMBO Journal, 2018Co-Authors: Maja Radulovic, Antonino Bongiovanni, Kay Oliver Schink, Viola Nahse, Eva Maria Wenzel, Frank LafontAbstract:Abstract Although Lysosomes perform a number of essential cellular functions, damaged Lysosomes represent a potential hazard to the cell. Such Lysosomes are therefore engulfed by autophagic Membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin‐3. Here, we show that, under various conditions that cause injury to the Lysosome Membrane, components of the endosomal sorting complex required for transport (ESCRT)‐I, ESCRT‐II, and ESCRT‐III are recruited. This recruitment occurs before that of Galectin‐3 and the lysophagy machinery. Subunits of the ESCRT‐III complex show a particularly prominent recruitment, which depends on the ESCRT‐I component TSG101 and the TSG101‐ and ESCRT‐III‐binding protein ALIX. Interference with ESCRT recruitment abolishes Lysosome repair and causes otherwise reversible Lysosome damage to become cell lethal. Vacuoles containing the intracellular pathogen Coxiella burnetii show reversible ESCRT recruitment, and interference with this recruitment reduces intravacuolar bacterial replication. We conclude that the cell is equipped with an endogenous mechanism for Lysosome repair which protects against lysosomal damage‐induced cell death but which also provides a potential advantage for intracellular pathogens.
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escrt mediated Lysosome repair precedes lysophagy and promotes cell survival
bioRxiv, 2018Co-Authors: Maja Radulovic, Antonino Bongiovanni, Kay Oliver Schink, Viola Nahse, Eva Maria Wenzel, Frank Lafont, Harald Alfred StenmarkAbstract:Although Lysosomes perform a number of essential cellular functions, damaged Lysosomes represent a potential hazard. Such Lysosomes are therefore engulfed by autophagic Membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin-3. Here we show that, under various conditions that cause injury to the Lysosome Membrane, components of the endosomal sorting complex required for transport (ESCRT) machinery are recruited. This recruitment occurs before that of Galectin-3 and the lysophagy machinery. Subunits of the ESCRT-III complex show a particularly prominent recruitment, which depends on the ESCRT-I component TSG101 and the TSG101- and ESCRT-III-binding protein ALIX. Interference with ESCRT recruitment abolishes Lysosome repair and causes otherwise reversible Lysosome damage to become cell lethal. Vacuoles containing the intracellular pathogen Coxiella burnetii show reversible ESCRT recruitment, and interference with this recruitment reduces intravacuolar bacterial replication. We conclude that the cell is equipped with an endogenous mechanism for Lysosome repair which protects against lysosomal damage-induced cell death but which also provides a potential advantage for intracellular pathogens.
Scott D Emr - One of the best experts on this subject based on the ideXlab platform.
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retrograde trafficking from the vacuole Lysosome Membrane
Autophagy, 2018Co-Authors: Sho W Suzuki, Scott D EmrAbstract:Membrane protein recycling is a fundamental process from yeast to humans. The Lysosome (or vacuole in yeast) receives Membrane proteins from the secretory, endocytic, and macroautophagy/autophagy pathways. Although some of these Membrane proteins appear to be recycled, the molecular mechanisms underlying this retrograde trafficking are poorly understood. Our recent study revealed that the transMembrane autophagy protein Atg27 is recycled from the vacuole Membrane using a 2-step recycling process. First, the Snx4 complex recycles Atg27 from the vacuole to the endosome. Then, the retromer complex mediates endosome-to-Golgi retrograde transport. Thus, 2 distinct protein complexes facilitate the sequential retrograde trafficking for Atg27. As far as we know, Atg27 is the first physiological substrate for the vacuole-to-endosome retrograde trafficking pathway.
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Membrane protein recycling from the vacuole Lysosome Membrane
Journal of Cell Biology, 2018Co-Authors: Sho W Suzuki, Scott D EmrAbstract:The Lysosome (or vacuole in yeast) is the central organelle responsible for cellular degradation and nutrient storage. Lysosomes receive cargo from the secretory, endocytic, and autophagy pathways. Many of these proteins and lipids are delivered to the Lysosome Membrane, and some are degraded in the Lysosome lumen, whereas others appear to be recycled through unknown pathways. In this study, we identify the transMembrane autophagy protein Atg27 as a physiological cargo recycled from the vacuole. We reveal that Atg27 is delivered to the vacuole Membrane and then recycled using a two-step recycling process. First, Atg27 is recycled from the vacuole to the endosome via the Snx4 complex and then from the endosome to the Golgi via the retromer complex. During the process of vacuole-to-endosome retrograde trafficking, Snx4 complexes assemble on the vacuolar surface and recognize specific residues in the cytoplasmic tail of Atg27. This novel pathway maintains the normal composition and function of the vacuole Membrane.
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escrts function directly on the Lysosome Membrane to downregulate ubiquitinated lysosomal Membrane proteins
eLife, 2017Co-Authors: Lu Zhu, Jeff R Jorgensen, Yashan Chuang, Scott D EmrAbstract:The Lysosome plays an important role in maintaining cellular nutrient homeostasis. Regulation of nutrient storage can occur by the ubiquitination of certain transporters that are then sorted into the Lysosome lumen for degradation. To better understand the underlying mechanism of this process, we performed genetic screens to identify components of the sorting machinery required for vacuole Membrane protein degradation. These screens uncovered genes that encode a ubiquitin ligase complex, components of the PtdIns 3-kinase complex, and the ESCRT machinery. We developed a novel ubiquitination system, Rapamycin-Induced Degradation (RapiDeg), to test the sorting defects caused by these mutants. These tests revealed that ubiquitinated vacuole Membrane proteins recruit ESCRTs to the vacuole surface, where they mediate cargo sorting and direct cargo delivery into the vacuole lumen. Our findings demonstrate that the ESCRTs can function at both the late endosome and the vacuole Membrane to mediate cargo sorting and intra-luminal vesicle formation. DOI: http://dx.doi.org/10.7554/eLife.26403.001
Frank Lafont - One of the best experts on this subject based on the ideXlab platform.
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escrt mediated Lysosome repair precedes lysophagy and promotes cell survival
The EMBO Journal, 2018Co-Authors: Maja Radulovic, Antonino Bongiovanni, Kay Oliver Schink, Viola Nahse, Eva Maria Wenzel, Frank LafontAbstract:Abstract Although Lysosomes perform a number of essential cellular functions, damaged Lysosomes represent a potential hazard to the cell. Such Lysosomes are therefore engulfed by autophagic Membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin‐3. Here, we show that, under various conditions that cause injury to the Lysosome Membrane, components of the endosomal sorting complex required for transport (ESCRT)‐I, ESCRT‐II, and ESCRT‐III are recruited. This recruitment occurs before that of Galectin‐3 and the lysophagy machinery. Subunits of the ESCRT‐III complex show a particularly prominent recruitment, which depends on the ESCRT‐I component TSG101 and the TSG101‐ and ESCRT‐III‐binding protein ALIX. Interference with ESCRT recruitment abolishes Lysosome repair and causes otherwise reversible Lysosome damage to become cell lethal. Vacuoles containing the intracellular pathogen Coxiella burnetii show reversible ESCRT recruitment, and interference with this recruitment reduces intravacuolar bacterial replication. We conclude that the cell is equipped with an endogenous mechanism for Lysosome repair which protects against lysosomal damage‐induced cell death but which also provides a potential advantage for intracellular pathogens.
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escrt mediated Lysosome repair precedes lysophagy and promotes cell survival
bioRxiv, 2018Co-Authors: Maja Radulovic, Antonino Bongiovanni, Kay Oliver Schink, Viola Nahse, Eva Maria Wenzel, Frank Lafont, Harald Alfred StenmarkAbstract:Although Lysosomes perform a number of essential cellular functions, damaged Lysosomes represent a potential hazard. Such Lysosomes are therefore engulfed by autophagic Membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin-3. Here we show that, under various conditions that cause injury to the Lysosome Membrane, components of the endosomal sorting complex required for transport (ESCRT) machinery are recruited. This recruitment occurs before that of Galectin-3 and the lysophagy machinery. Subunits of the ESCRT-III complex show a particularly prominent recruitment, which depends on the ESCRT-I component TSG101 and the TSG101- and ESCRT-III-binding protein ALIX. Interference with ESCRT recruitment abolishes Lysosome repair and causes otherwise reversible Lysosome damage to become cell lethal. Vacuoles containing the intracellular pathogen Coxiella burnetii show reversible ESCRT recruitment, and interference with this recruitment reduces intravacuolar bacterial replication. We conclude that the cell is equipped with an endogenous mechanism for Lysosome repair which protects against lysosomal damage-induced cell death but which also provides a potential advantage for intracellular pathogens.
Kay Oliver Schink - One of the best experts on this subject based on the ideXlab platform.
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escrt mediated Lysosome repair precedes lysophagy and promotes cell survival
The EMBO Journal, 2018Co-Authors: Maja Radulovic, Antonino Bongiovanni, Kay Oliver Schink, Viola Nahse, Eva Maria Wenzel, Frank LafontAbstract:Abstract Although Lysosomes perform a number of essential cellular functions, damaged Lysosomes represent a potential hazard to the cell. Such Lysosomes are therefore engulfed by autophagic Membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin‐3. Here, we show that, under various conditions that cause injury to the Lysosome Membrane, components of the endosomal sorting complex required for transport (ESCRT)‐I, ESCRT‐II, and ESCRT‐III are recruited. This recruitment occurs before that of Galectin‐3 and the lysophagy machinery. Subunits of the ESCRT‐III complex show a particularly prominent recruitment, which depends on the ESCRT‐I component TSG101 and the TSG101‐ and ESCRT‐III‐binding protein ALIX. Interference with ESCRT recruitment abolishes Lysosome repair and causes otherwise reversible Lysosome damage to become cell lethal. Vacuoles containing the intracellular pathogen Coxiella burnetii show reversible ESCRT recruitment, and interference with this recruitment reduces intravacuolar bacterial replication. We conclude that the cell is equipped with an endogenous mechanism for Lysosome repair which protects against lysosomal damage‐induced cell death but which also provides a potential advantage for intracellular pathogens.
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escrt mediated Lysosome repair precedes lysophagy and promotes cell survival
bioRxiv, 2018Co-Authors: Maja Radulovic, Antonino Bongiovanni, Kay Oliver Schink, Viola Nahse, Eva Maria Wenzel, Frank Lafont, Harald Alfred StenmarkAbstract:Although Lysosomes perform a number of essential cellular functions, damaged Lysosomes represent a potential hazard. Such Lysosomes are therefore engulfed by autophagic Membranes in the process known as lysophagy, which is initiated by recognition of luminal glycoprotein domains by cytosolic lectins such as Galectin-3. Here we show that, under various conditions that cause injury to the Lysosome Membrane, components of the endosomal sorting complex required for transport (ESCRT) machinery are recruited. This recruitment occurs before that of Galectin-3 and the lysophagy machinery. Subunits of the ESCRT-III complex show a particularly prominent recruitment, which depends on the ESCRT-I component TSG101 and the TSG101- and ESCRT-III-binding protein ALIX. Interference with ESCRT recruitment abolishes Lysosome repair and causes otherwise reversible Lysosome damage to become cell lethal. Vacuoles containing the intracellular pathogen Coxiella burnetii show reversible ESCRT recruitment, and interference with this recruitment reduces intravacuolar bacterial replication. We conclude that the cell is equipped with an endogenous mechanism for Lysosome repair which protects against lysosomal damage-induced cell death but which also provides a potential advantage for intracellular pathogens.
