scholarly journals A sterol-enriched vacuolar microdomain mediates stationary phase lipophagy in budding yeast

2014 ◽  
Vol 206 (3) ◽  
pp. 357-366 ◽  
Author(s):  
Chao-Wen Wang ◽  
Yu-Hsuan Miao ◽  
Yi-Shun Chang
Keyword(s):  
Endoplasmic Reticulum ◽  
Stationary Phase ◽  
Lipid Droplets ◽  
Physiological State ◽  
Lipid Homeostasis ◽  
Cellular Lipid ◽  
Sterol Esters ◽  
Selective Autophagy ◽  
The Core ◽  
Atg Proteins

Stationary phase (stat-phase) is a poorly understood physiological state under which cells arrest proliferation and acquire resistance to multiple stresses. Lipid droplets (LDs), organelles specialized for cellular lipid homeostasis, increase in size and number at the onset of stat-phase. However, little is known about the dynamics of LDs under this condition. In this paper, we reveal the passage of LDs from perinuclear endoplasmic reticulum association to entry into vacuoles during the transition to stat-phase. We show that the process requires the core autophagy machinery and a subset of autophagy-related (Atg) proteins involved in selective autophagy. Notably, the process that we term stat-phase lipophagy is mediated through a sterol-enriched vacuolar microdomain whose formation and integrity directly affect LD translocation. Intriguingly, cells defective in stat-phase lipophagy showed disrupted vacuolar microdomains, implying that LD contents, likely sterol esters, contribute to the maintenance of vacuolar microdomains. Together, we propose a feed-forward loop in which lipophagy stimulates vacuolar microdomain formation, which in turn promotes lipophagy during stat-phase.

scholarly journals A Decade of Mighty Lipophagy: What We Know and What Facts We Need to Know?

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Muhammad Babar Khawar ◽  
Muddasir Hassan Abbasi ◽  
Mussarat Rafiq ◽  
Naila Naz ◽  
Rabia Mehmood ◽  
...  
Keyword(s):  
Cell Death ◽  
Lipid Droplets ◽  
Lysosomal Enzymes ◽  
Lipid Homeostasis ◽  
Cellular Lipid ◽  
Biological Functions ◽  
Lysosomal Function ◽  
Selective Autophagy ◽  
Cellular Components ◽  
Different Levels

Lipids are integral cellular components that act as substrates for energy provision, signaling molecules, and essential constituents of biological membranes along with a variety of other biological functions. Despite their significance, lipid accumulation may result in lipotoxicity, impair autophagy, and lysosomal function that may lead to certain diseases and metabolic syndromes like obesity and even cell death. Therefore, these lipids are continuously recycled and redistributed by the process of selective autophagy specifically termed as lipophagy. This selective form of autophagy employs lysosomes for the maintenance of cellular lipid homeostasis. In this review, we have reviewed the current literature about how lipid droplets (LDs) are recruited towards lysosomes, cross-talk between a variety of autophagy receptors present on LD surface and lysosomes, and lipid hydrolysis by lysosomal enzymes. In addition to it, we have tried to answer most of the possible questions related to lipophagy regulation at different levels. Moreover, in the last part of this review, we have discussed some of the pathological states due to the accumulation of these LDs and their possible treatments under the light of currently available findings.

scholarly journals Nitrogen starvation and stationary phase lipophagy have distinct molecular mechanisms

2020 ◽  
Author(s):  
Ravinder Kumar ◽  
Muhammad Arifur Rahman ◽  
Taras Y. Nazarko
Keyword(s):  
Lipid Droplets ◽  
Molecular Mechanisms ◽  
Nitrogen Starvation ◽  
S Phase ◽  
Carbon Limitation ◽  
Intracellular Lipid ◽  
Selective Autophagy ◽  
The Core ◽  
Vacuole Fusion ◽  
N Starvation

AbstractIn yeast, the selective autophagy of intracellular lipid droplets (LDs) or lipophagy can be induced by either nitrogen (N) starvation or carbon limitation (e.g. in the stationary (S) phase). We developed the yeast, Komagataella phaffii (formerly Pichia pastoris), as a new lipophagy model and compared the N-starvation and S-phase lipophagy in over 30 autophagy-related mutants using the Erg6-GFP processing assay. Surprisingly, two lipophagy pathways had hardly overlapping stringent molecular requirements. While the N-starvation lipophagy strictly depended on the core autophagic machinery (Atg1-Atg9, Atg18 and Vps15), vacuole fusion machinery (Vam7 and Ypt7) and vacuolar proteolysis (proteinases A and B), only Atg6 and proteinases A and B were essential for the S-phase lipophagy. The rest of the proteins were only partially required in the S-phase. Moreover, we isolated the prl1 (for positive regulator of lipophagy 1) mutant affected in the S-phase lipophagy but not N-starvation lipophagy. The prl1 defect was at a stage of delivery of the LDs from the cytoplasm to the vacuole further supporting mechanistically different nature of the two lipophagy pathways. Taken together, our results suggest that N-starvation and S-phase lipophagy have distinct molecular mechanisms.

scholarly journals Recent Advances in Single-Particle Electron Microscopic Analysis of Autophagy Degradation Machinery

2020 ◽  
Vol 21 (21) ◽  
pp. 8051
Author(s):  
Yiu Wing Sunny Cheung ◽  
Sung-Eun Nam ◽  
Calvin K. Yip
Keyword(s):  
Single Particle ◽  
Membrane Vesicle ◽  
Microscopic Analysis ◽  
Degradation Process ◽  
Electron Microscopic ◽  
Major Pathway ◽  
Selective Autophagy ◽  
Selective Degradation ◽  
The Core ◽  
Atg Proteins

Macroautophagy (also known as autophagy) is a major pathway for selective degradation of misfolded/aggregated proteins and damaged organelles and non-selective degradation of cytoplasmic constituents for the generation of power during nutrient deprivation. The multi-step degradation process, from sequestering cytoplasmic cargo into the double-membrane vesicle termed autophagosome to the delivery of the autophagosome to the lysosome or lytic vacuole for breakdown, is mediated by the core autophagy machinery composed of multiple Atg proteins, as well as the divergent sequence family of selective autophagy receptors. Single-particle electron microscopy (EM) is a molecular imaging approach that has become an increasingly important tool in the structural characterization of proteins and macromolecular complexes. This article summarizes the contributions single-particle EM have made in advancing our understanding of the core autophagy machinery and selective autophagy receptors. We also discuss current technical challenges and roadblocks, as well as look into the future of single-particle EM in autophagy research.

scholarly journals Autophagy in Neurons

2019 ◽  
Vol 35 (1) ◽  
pp. 477-500 ◽  
Author(s):  
Andrea K.H. Stavoe ◽  
Erika L.F. Holzbaur
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Neuronal Development ◽  
Selective Autophagy ◽  
The Core ◽  
Differentiated Cells ◽  
Neuronal Homeostasis ◽  
Core Components ◽  
Cellular Organelles

Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.

scholarly journals The yeast FIT2 homologs are necessary to maintain cellular proteostasis and membrane lipid homeostasis

2020 ◽  
Vol 133 (21) ◽  
pp. jcs248526 ◽  
Author(s):  
Wei Sheng Yap ◽  
Peter Shyu ◽  
Maria Laura Gaspar ◽  
Stephen A. Jesch ◽  
Charlie Marvalim ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Membrane Lipid ◽  
Model System ◽  
Lipid Homeostasis ◽  
Compensatory Mechanism ◽  
Unfolded Protein ◽  
Protein Response

ABSTRACTLipid droplets (LDs) are implicated in conditions of lipid and protein dysregulation. The fat storage-inducing transmembrane (FIT; also known as FITM) family induces LD formation. Here, we establish a model system to study the role of the Saccharomyces cerevisiae FIT homologues (ScFIT), SCS3 and YFT2, in the proteostasis and stress response pathways. While LD biogenesis and basal endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) remain unaltered in ScFIT mutants, SCS3 was found to be essential for proper stress-induced UPR activation and for viability in the absence of the sole yeast UPR transducer IRE1. Owing to not having a functional UPR, cells with mutated SCS3 exhibited an accumulation of triacylglycerol within the ER along with aberrant LD morphology, suggesting that there is a UPR-dependent compensatory mechanism that acts to mitigate lack of SCS3. Additionally, SCS3 was necessary to maintain phospholipid homeostasis. Strikingly, global protein ubiquitylation and the turnover of both ER and cytoplasmic misfolded proteins is impaired in ScFITΔ cells, while a screen for interacting partners of Scs3 identifies components of the proteostatic machinery as putative targets. Together, our data support a model where ScFITs play an important role in lipid metabolism and proteostasis beyond their defined roles in LD biogenesis.This article has an associated First Person interview with the first author of the paper.

scholarly journals Autophagosomes contribute to intracellular lipid distribution in enterocytes

2014 ◽  
Vol 25 (1) ◽  
pp. 118-132 ◽  
Author(s):  
Salem Ait Khaldoun ◽  
Marc-Alexandre Emond-Boisjoly ◽  
Danielle Chateau ◽  
Véronique Carrière ◽  
Michel Lacasa ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Lipid Homeostasis ◽  
Coat Proteins ◽  
Cellular Lipid ◽  
Intracellular Lipid ◽  
Lipid Trafficking ◽  
Complex Lipid ◽  
Lipid Micelles ◽  
Er Membrane

Enterocytes, the intestinal absorptive cells, have to deal with massive alimentary lipids upon food consumption. They orchestrate complex lipid-trafficking events that lead to the secretion of triglyceride-rich lipoproteins and/or the intracellular transient storage of lipids as lipid droplets (LDs). LDs originate from the endoplasmic reticulum (ER) membrane and are mainly composed of a triglyceride (TG) and cholesterol-ester core surrounded by a phospholipid and cholesterol monolayer and specific coat proteins. The pivotal role of LDs in cellular lipid homeostasis is clearly established, but processes regulating LD dynamics in enterocytes are poorly understood. Here we show that delivery of alimentary lipid micelles to polarized human enterocytes induces an immediate autophagic response, accompanied by phosphatidylinositol-3-phosphate appearance at the ER membrane. We observe a specific and rapid capture of newly synthesized LD at the ER membrane by nascent autophagosomal structures. By combining pharmacological and genetic approaches, we demonstrate that autophagy is a key player in TG targeting to lysosomes. Our results highlight the yet-unraveled role of autophagy in the regulation of TG distribution, trafficking, and turnover in human enterocytes.

scholarly journals Peroxisome Size Provides Insights into the Function of Autophagy-related Proteins

2009 ◽  
Vol 20 (17) ◽  
pp. 3828-3839 ◽  
Author(s):  
Taras Y. Nazarko ◽  
Jean-Claude Farré ◽  
Suresh Subramani
Keyword(s):  
Model System ◽  
Intracellular Bacteria ◽  
Major Pathway ◽  
Selective Autophagy ◽  
Intracellular Degradation ◽  
The Core ◽  
Atg Proteins ◽  
Related Proteins ◽  
Assembly Site ◽  
Yeast Model

Autophagy is a major pathway of intracellular degradation mediated by formation of autophagosomes. Recently, autophagy was implicated in the degradation of intracellular bacteria, whose size often exceeds the capacity of normal autophagosomes. However, the adaptations of the autophagic machinery for sequestration of large cargos were unknown. Here we developed a yeast model system to study the effect of cargo size on the requirement of autophagy-related (Atg) proteins. We controlled the size of peroxisomes before their turnover by pexophagy, the selective autophagy of peroxisomes, and found that peroxisome size determines the requirement of Atg11 and Atg26. Small peroxisomes can be degraded without these proteins. However, Atg26 becomes essential for degradation of medium peroxisomes. Additionally, the pexophagy-specific phagophore assembly site, organized by the dual interaction of Atg30 with functionally active Atg11 and Atg17, becomes essential for degradation of large peroxisomes. In contrast, Atg28 is partially required for all autophagy-related pathways independent of cargo size, suggesting it is a component of the core autophagic machinery. As a rule, the larger the cargo, the more cargo-specific Atg proteins become essential for its sequestration.

scholarly journals Recruitment of Peroxin14 to lipid droplets affects triglyceride storage in Drosophila

2021 ◽  
Author(s):  
Matthew Anderson-Baron ◽  
Kazuki Ueda ◽  
Julie Haskins ◽  
Sarah C Hughes ◽  
Andrew Simmonds
Keyword(s):  
Neutral Lipid ◽  
Lipid Droplet ◽  
Functional Role ◽  
Lipid Droplets ◽  
Droplet Surface ◽  
Lipid Homeostasis ◽  
Cellular Lipid ◽  
Peroxisome Biogenesis ◽  
Drosophila Cells

The activity of multiple organelles must be coordinated to ensure cellular lipid homeostasis. This includes the peroxisomes which metabolise certain lipids and lipid droplets which act as neutral lipid storage centres. Direct organellar contact between peroxisomes and lipid droplets has been observed, and interaction between proteins associated with the membranes of these organelles has been shown, but the functional role of these interactions is not clear. In Drosophila cells, we identified a novel localization of a subset of three transmembrane Peroxin proteins (Peroxin3, Peroxin13, and Peroxin14), normally required for peroxisome biogenesis, to newly formed lipid droplets. This event was not linked to significant changes in peroxisome size or number, nor was recruitment of other Peroxin proteins or mature peroxisomes observed. The presence of these Peroxin proteins at lipid droplets influences their function as changes in the relative levels of Peroxin14 associated with the lipid droplet surface directly affected the presence of regulatory perilipin and lipases with corresponding effects on triglyceride storage.

scholarly journals Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism

2020 ◽  
Vol 3 (6) ◽  
pp. e201900521 ◽  
Author(s):  
Esteban Gutierrez ◽  
Dieter Lütjohann ◽  
Anja Kerksiek ◽  
Marietta Fabiano ◽  
Naoto Oikawa ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Amyloid Precursor Protein ◽  
Lipid Droplets ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Lipid Homeostasis ◽  
Amyloid Β Peptide ◽  
Cellular Lipid ◽  
Additional Protein ◽  
X Receptors

Presenilins (PS) are the catalytic components of γ-secretase complexes that mediate intramembrane proteolysis. Mutations in the PS genes are a major cause of familial early-onset Alzheimer disease and affect the cleavage of the amyloid precursor protein, thereby altering the production of the amyloid β-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of γ-secretase. Here, we demonstrate that inhibition of γ-secretase causes dysregulation of cellular lipid homeostasis, including up-regulation of liver X receptors, and complex changes in the cellular lipid composition. Genetic and pharmacological inhibition of γsecretase leads to strong accumulation of cytoplasmic lipid droplets, associated with increased levels of acylglycerols, but lowered cholesteryl esters. Furthermore, accumulation of lipid droplets was augmented by increasing levels of amyloid precursor protein C-terminal fragments, indicating a critical involvement of this γ-secretase substrate. Together, these data provide a mechanism that functionally connects γ-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of γ-secretase in cells critical for lipid homeostasis in the brain.

scholarly journals Lipid droplet autophagy in the yeast Saccharomyces cerevisiae

2014 ◽  
Vol 25 (2) ◽  
pp. 290-301 ◽  
Author(s):  
Tim van Zutphen ◽  
Virginia Todde ◽  
Rinse de Boer ◽  
Martin Kreim ◽  
Harald F. Hofbauer ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Lipid Droplets ◽  
De Novo ◽  
Close Association ◽  
Acid Synthesis ◽  
Lipid Homeostasis ◽  
Yeast Saccharomyces Cerevisiae ◽  
Hormonal Stimulation ◽  
Steryl Esters ◽  
The Core

Cytosolic lipid droplets (LDs) are ubiquitous organelles in prokaryotes and eukaryotes that play a key role in cellular and organismal lipid homeostasis. Triacylglycerols (TAGs) and steryl esters, which are stored in LDs, are typically mobilized in growing cells or upon hormonal stimulation by LD-associated lipases and steryl ester hydrolases. Here we show that in the yeast Saccharomyces cerevisiae, LDs can also be turned over in vacuoles/lysosomes by a process that morphologically resembles microautophagy. A distinct set of proteins involved in LD autophagy is identified, which includes the core autophagic machinery but not Atg11 or Atg20. Thus LD autophagy is distinct from endoplasmic reticulum–autophagy, pexophagy, or mitophagy, despite the close association between these organelles. Atg15 is responsible for TAG breakdown in vacuoles and is required to support growth when de novo fatty acid synthesis is compromised. Furthermore, none of the core autophagy proteins, including Atg1 and Atg8, is required for LD formation in yeast.

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