scholarly journals RAB18 impacts autophagy via lipid droplet-derived lipid transfer and is rescued by ATG9A

2018 ◽  
Author(s):  
Fazilet Bekbulat ◽  
Daniel Schmitt ◽  
Anne Feldmann ◽  
Heike Huesmann ◽  
Stefan Eimer ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Transmembrane Protein ◽  
Degradation Pathway ◽  
Rab Gtpase ◽  
Lipid Transfer ◽  
Lysosomal Degradation ◽  
Autophagosome Formation ◽  
Autophagic Activity ◽  
Rescue Mechanism

AbstractAutophagy is a lysosomal degradation pathway that mediates protein and organelle turnover and maintains cellular homeostasis. Autophagosomes transport cargo to lysosomes and their formation is dependent on an appropriate lipid supply. Here, we show that the knockout of the RAB GTPase RAB18 interferes with lipid droplet (LD) metabolism, resulting in an impaired fatty acid mobilization. The reduced LD-derived lipid availability influences autophagy and provokes adaptive modifications of the autophagy network, which include increased ATG2B expression and ATG12-ATG5 conjugate formation as well as enhanced ATG2B and ATG9A phosphorylation. Phosphorylation of ATG9A directs this transmembrane protein to the site of autophagosome formation and this particular modification is sufficient to rescue autophagic activity under basal conditions in the absence of RAB18. However, it is incapable of enabling an increased autophagy under inductive conditions. Thus, we illustrate the role of RAB18 in connecting LDs and autophagy, further emphasize the importance of LD-derived lipids for the degradative pathway, and characterize an ATG9A phosphorylation-dependent autophagy rescue mechanism as an adaptive response that maintains autophagy under conditions of reduced LD-derived lipid availability.

scholarly journals An Intervention Target for Myocardial Fibrosis: Autophagy

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Chunmiao Lu ◽  
Yusong Yang ◽  
Yaping Zhu ◽  
Shichao Lv ◽  
Junping Zhang
Keyword(s):  
Cardiovascular Diseases ◽  
Myocardial Fibrosis ◽  
Collagen Synthesis ◽  
Degradation Pathway ◽  
Lysosomal Degradation ◽  
Metabolic Imbalance

Myocardial fibrosis (MF) is the result of metabolic imbalance of collagen synthesis and metabolism, which is widespread in various cardiovascular diseases. Autophagy is a lysosomal degradation pathway which is highly conserved. In recent years, research on autophagy has been increasing and the researchers have also become cumulatively aware of the specified association between autophagy and MF. This review highlights the role of autophagy in MF and the potential effects through the administration of medicine.

scholarly journals Autophagosome formation in relation to the endoplasmic reticulum

2020 ◽  
Vol 27 (1) ◽  
Author(s):  
Yo-hei Yamamoto ◽  
Takeshi Noda
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
De Novo ◽  
Transmembrane Protein ◽  
Lipid Transfer ◽  
Membrane Structures ◽  
Autophagosome Formation ◽  
Selective Autophagy ◽  
The Relationship ◽  
Er Membrane

Abstract Autophagy is a process in which a myriad membrane structures called autophagosomes are formed de novo in a single cell, which deliver the engulfed substrates into lysosomes for degradation. The size of the autophagosomes is relatively uniform in non-selective autophagy and variable in selective autophagy. It has been recently established that autophagosome formation occurs near the endoplasmic reticulum (ER). In this review, we have discussed recent advances in the relationship between autophagosome formation and endoplasmic reticulum. Autophagosome formation occurs near the ER subdomain enriched with phospholipid synthesizing enzymes like phosphatidylinositol synthase (PIS)/CDP-diacylglycerol-inositol 3-phosphatidyltransferase (CDIPT) and choline/ethanolamine phosphotransferase 1 (CEPT1). Autophagy-related protein 2 (Atg2), which is involved in autophagosome formation has a lipid transfer capacity and is proposed to directly transfer the lipid molecules from the ER to form autophagosomes. Vacuole membrane protein 1 (VMP1) and transmembrane protein 41b (TMEM41b) are ER membrane proteins that are associated with the formation of the subdomain. Recently, we have reported that an uncharacterized ER membrane protein possessing the DNAJ domain, called ERdj8/DNAJC16, is associated with the regulation of the size of autophagosomes. The localization of ERdj8/DNAJC16 partially overlaps with the PIS-enriched ER subdomain, thereby implying its association with autophagosome size determination.

scholarly journals Protein crowding mediates membrane remodeling in upstream ESCRT-induced formation of intraluminal vesicles

2020 ◽  
Vol 117 (46) ◽  
pp. 28614-28624
Author(s):  
Susanne Liese ◽  
Eva Maria Wenzel ◽  
Ingrid Kjos ◽  
Rossana Rojas Molina ◽  
Sebastian W. Schultz ◽  
...  
Keyword(s):  
Degradation Pathway ◽  
Bending Rigidity ◽  
Lysosomal Degradation ◽  
Endosomal Sorting ◽  
Electron Microscopy Analysis ◽  
Steep Decline ◽  
Microscopy Analysis ◽  
Protein Crowding ◽  
Membrane Shape

As part of the lysosomal degradation pathway, the endosomal sorting complexes required for transport (ESCRT-0 to -III/VPS4) sequester receptors at the endosome and simultaneously deform the membrane to generate intraluminal vesicles (ILVs). Whereas ESCRT-III/VPS4 have an established function in ILV formation, the role of upstream ESCRTs (0 to II) in membrane shape remodeling is not understood. Combining experimental measurements and electron microscopy analysis of ESCRT-III–depleted cells with a mathematical model, we show that upstream ESCRT-induced alteration of the Gaussian bending rigidity and their crowding in concert with the transmembrane cargo on the membrane induce membrane deformation and facilitate ILV formation: Upstream ESCRT-driven budding does not require ATP consumption as only a small energy barrier needs to be overcome. Our model predicts that ESCRTs do not become part of the ILV, but localize with a high density at the membrane neck, where the steep decline in the Gaussian curvature likely triggers ESCRT-III/VPS4 assembly to enable neck constriction and scission.

scholarly journals Lipid Body Dynamics in Shoot Meristems: Production, Enlargement, and Putative Organellar Interactions and Plasmodesmal Targeting

2021 ◽  
Vol 12 ◽  
Author(s):  
Manikandan Veerabagu ◽  
Päivi L. H. Rinne ◽  
Morten Skaugen ◽  
Laju K. Paul ◽  
Christiaan van der Schoot
Keyword(s):  
Gene Expression ◽  
Lipid Droplet ◽  
Major Gene ◽  
Lipid Body ◽  
Rab Gtpase ◽  
Embryonic Cells ◽  
Interacting Protein ◽  
Associated Proteins ◽  
Myosin Xi

Post-embryonic cells contain minute lipid bodies (LBs) that are transient, mobile, engage in organellar interactions, and target plasmodesmata (PD). While LBs can deliver γ-clade 1,3-β-glucanases to PD, the nature of other cargo is elusive. To gain insight into the poorly understood role of LBs in meristems, we investigated their dynamics by microscopy, gene expression analyzes, and proteomics. In developing buds, meristems accumulated LBs, upregulated several LB-specific OLEOSIN genes and produced OLEOSINs. During bud maturation, the major gene OLE6 was strongly downregulated, OLEOSINs disappeared from bud extracts, whereas lipid biosynthesis genes were upregulated, and LBs were enlarged. Proteomic analyses of the LB fraction of dormant buds confirmed that OLEOSINs were no longer present. Instead, we identified the LB-associated proteins CALEOSIN (CLO1), Oil Body Lipase 1 (OBL1), Lipid Droplet Interacting Protein (LDIP), Lipid Droplet Associated Protein1a/b (LDAP1a/b) and LDAP3a/b, and crucial components of the OLEOSIN-deubiquitinating and degradation machinery, such as PUX10 and CDC48A. All mRFP-tagged LDAPs localized to LBs when transiently expressed in Nicotiana benthamiana. Together with gene expression analyzes, this suggests that during bud maturation, OLEOSINs were replaced by LDIP/LDAPs at enlarging LBs. The LB fraction contained the meristem-related actin7 (ACT7), “myosin XI tail-binding” RAB GTPase C2A, an LB/PD-associated γ-clade 1,3-β-glucanase, and various organelle- and/or PD-localized proteins. The results are congruent with a model in which LBs, motorized by myosin XI-k/1/2, traffic on F-actin, transiently interact with other organelles, and deliver a diverse cargo to PD.

scholarly journals Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jennifer Jung ◽  
Arnab Nayak ◽  
Véronique Schaeffer ◽  
Tatjana Starzetz ◽  
Achim K Kirsch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Membrane Trafficking ◽  
Gene Locus ◽  
Kinase Activity ◽  
Degradation Pathway ◽  
Rab Gtpase ◽  
Rab Gtpases ◽  
Mrna Expression Analysis ◽  
Different Populations

Autophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2. Collectively, we established SMCR8 as multifaceted negative autophagy regulator.

scholarly journals Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer’s Disease-associated Genes

2021 ◽  
Author(s):  
Matthew J. Moulton ◽  
Scott Barish ◽  
Isha Ralhan ◽  
Jinlan Chang ◽  
Lindsey D. Goodman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Droplet ◽  
Critical Role ◽  
Lipid Transfer ◽  
Lipid Droplet Formation ◽  
Apoe Receptor ◽  
Disease Associated Genes

SummaryA growing list of Alzheimer’s disease (AD) genetic risk factors is being identified, but the contribution of these genetic mutations to disease remains largely unknown. Accumulating data support a role of lipid dysregulation and excessive ROS in the etiology of AD. Here, we identified cell-specific roles for eight AD risk-associated genes in ROS-induced glial lipid droplet (LD) formation. We demonstrate that ROS-induced glial LD formation requires two ABCA transporters (ABCA1 and ABCA7) in neurons, the APOE receptor (LRP1), endocytic genes (PICALM, CD2AP, and AP2A2) in glia, and retromer genes (VPS26 and VPS35) in both neurons and glia. Moreover, ROS strongly enhances Aβ42-toxicity in flies and Aβ42-plaque formation in mice. Finally, an ABCA1-activating peptide restores glial LD formation in the APOE4-associated loss of LD. This study places AD risk factors in a neuron-to-glia lipid transfer pathway with a critical role in protecting neurons from ROS-induced toxicity.

scholarly journals The Impact of Autophagy on The Differentiation of Immune Cells

2021 ◽  
Vol 6 (2) ◽  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Degradation Pathway ◽  
Lysosomal Degradation ◽  
Specific Mechanism ◽  
Multiple Functions ◽  
Selective Degradation ◽  
Proliferation And Differentiation ◽  
The Impact

Autophagy, as a conservative lysosomal degradation pathway, has been well studied for its multiple functions in the immune system. Autophagy has been gradually explored for the regulation of immune cell differentiation. In order to explore the specific mechanism, it is necessary to summarize the role of autophagy in the proliferation and differentiation of immune cells. It is summarized the effects of autophagy in some researches on the function and differentiation of immune cells by introducing the function of autophagy selective degradation. In this review, we discuss the effect of autophagy in the differentiation of immune cells.

scholarly journals The Atg8 Conjugation System Is Indispensable for Proper Development of Autophagic Isolation Membranes in Mice

2008 ◽  
Vol 19 (11) ◽  
pp. 4762-4775 ◽  
Author(s):  
Yu-shin Sou ◽  
Satoshi Waguri ◽  
Jun-ichi Iwata ◽  
Takashi Ueno ◽  
Tsutomu Fujimura ◽  
...  
Keyword(s):  
Essential Role ◽  
Degradation Pathway ◽  
Conjugation System ◽  
Autophagosome Formation ◽  
Gene Encoding ◽  
Genetic Studies ◽  
Evolutionarily Conserved ◽  
Deficient Mice ◽  
Mouse Genetic

Autophagy is an evolutionarily conserved bulk-protein degradation pathway in which isolation membranes engulf the cytoplasmic constituents, and the resulting autophagosomes transport them to lysosomes. Two ubiquitin-like conjugation systems, termed Atg12 and Atg8 systems, are essential for autophagosomal formation. In addition to the pathophysiological roles of autophagy in mammals, recent mouse genetic studies have shown that the Atg8 system is predominantly under the control of the Atg12 system. To clarify the roles of the Atg8 system in mammalian autophagosome formation, we generated mice deficient in Atg3 gene encoding specific E2 enzyme for Atg8. Atg3-deficient mice were born but died within 1 d after birth. Conjugate formation of mammalian Atg8 homologues was completely defective in the mutant mice. Intriguingly, Atg12–Atg5 conjugation was markedly decreased in Atg3-deficient mice, and its dissociation from isolation membranes was significantly delayed. Furthermore, loss of Atg3 was associated with defective process of autophagosome formation, including the elongation and complete closure of the isolation membranes, resulting in malformation of the autophagosomes. The results indicate the essential role of the Atg8 system in the proper development of autophagic isolation membranes in mice.

scholarly journals Septins are involved at the early stages of macroautophagy inS. cerevisiae

2016 ◽  
Author(s):  
Gaurav Barve ◽  
Shreyas Sridhar ◽  
Amol Aher ◽  
Sunaina Singh ◽  
Lakshmeesha K.N. ◽  
...  
Keyword(s):  
Membrane Vesicle ◽  
Degradation Pathway ◽  
Permissive Temperature ◽  
Autophagosome Formation ◽  
Double Membrane ◽  
Early Stages ◽  
Gtp Binding ◽  
Bud Neck ◽  
Ts Mutant

Autophagy is a conserved cellular degradation pathway wherein a double membrane vesicle, called as an autophagosome captures longlived proteins, damaged or superfluous organelles and delivers to the lysosome for degradation1. We have identified a novel role for septins in autophagy. Septins are GTP-binding proteins that localize at the bud-neck and are involved in cytokinesis in budding yeast2. We show that septins under autophagy prevalent conditions are majorly localized to the cytoplasm in the form of punctate structures. Further, we report that septins not only localize to pre-autophagosomal structure (PAS) but also to autophagosomes in the form of punctate structures. Interestingly, septins also form small non-canonical rings around PAS during autophagy. Furthermore, we observed that in one of the septin Ts" mutant,cdc10-5, the anterograde trafficking of Atg9 was affected at the non-permissive temperature (NPT). All these results suggest a role of septins in early stages of autophagy during autophagosome formation.

Towards unravelling the role of the lipid droplet-associated proteins perilipin, adipophilin, and TIP47 in hepatocellular carcinoma

2009 ◽  
Vol 47 (01) ◽  
Author(s):  
BK Straub ◽  
S Singer ◽  
J Lehmann-Koch ◽  
H Heid ◽  
E Specht ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Lipid Droplet ◽  
Associated Proteins
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