The Role of Lipids in the Control of Autophagy

Dall’Armi, Claudia; Devereaux, Kelly; Paolo, Gilbert Di

doi:10.1016/j.cub.2012.10.041

Cited by 253 publications

(253 citation statements)

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“…It has been proposed that altered lipid content (i.e., high cholesterol or ganglioside levels) may contribute to autophagy impairment. [20][21][22][23][24] On the other hand, the lipid that most significantly accumulates in neurons from ASMko mice is SM. 10 Hence, we directly tested whether SM accumulation was responsible for the autophagosome-lysosome alterations observed in the ASMko mice brain.…”

Section: Resultsmentioning

confidence: 99%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

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Section: Resultsmentioning

confidence: 99%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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“…Sphingolipids including ceramide, sphingosine, and S1P have been shown to stimulate macroautophagy (hereafter referred to as "autophagy") (36)(37)(38). As autophagy is a cell-autonomous defense mechanism against intracellular bacteria (39) and a relationship between autophagy and sphingosine metabolism is actively discussed in the field (40), we wondered whether LpSpl would modulate autophagy in human cells.…”

Section: Resultsmentioning

confidence: 99%

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

Rolando

Escoll

Nora

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

130

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Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens. Legionella pneumophila, an intracellular pathogen that can cause a severe pneumonia in humans, is able to modulate autophagy through the action of effector proteins that are translocated into the host cell by the pathogen's Dot/Icm type IV secretion system. Many of these effectors share structural and sequence similarity with eukaryotic proteins. Indeed, phylogenetic analyses have indicated their acquisition by horizontal gene transfer from a eukaryotic host. Here we report that L. pneumophila translocates the effector protein sphingosine-1 phosphate lyase (LpSpl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of LpSpl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that LpSpl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues. L. pneumophila triggers the reduction of several sphingolipids critical for macrophage function in an LpSpl-dependent and -independent manner. LpSpl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection. LpSpl was required for efficient infection of A/J mice, highlighting an important virulence role for this effector. Thus, we have uncovered a previously unidentified mechanism used by intracellular pathogens to inhibit autophagy, namely the disruption of host sphingolipid biosynthesis.Legionella pneumophila | sphingosine-1-phosphate lyase | autophagy | sphingolipids | virulence T he Gram-negative intracellular bacterium Legionella pneumophila is an opportunistic human pathogen responsible for Legionnaires' disease. The bacteria are naturally found in freshwater systems where they replicate within protozoan hosts (1). It is thought that the adaptation to replication within amoebas has equipped L. pneumophila with the factors required to replicate successfully within human macrophages following opportunistic infection (2). Through genome sequencing, we have discovered that L. pneumophila encodes a high number and variety of proteins similar in sequence to eukaryotic proteins that are never or rarely found in other prokaryotic genomes (3). Subsequent phylogenetic analyses have suggested that many of these proteins were acquired by horizontal gene transfer (3, 4). One of these proteins exhibits a high degree of similarity to eukaryotic sphingosine-1 phosphate lyase (SPL). The L. pneumophila SPL homolog (LpSpl encoded by gene lpp2128, lpg2176, or legS2) is conserved in all L. pneumophila strains sequenced to date, but absent from Legionella longbeachae (SI Appendix, Table S1). Phylogenetic analysis of SPL sequences showed that the L. pneumophila spl gene was most likely acquired early during evolution by horizontal gene transfer from a protozoan organism (4, 5). With the increase in genome sequences available...

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“…In the autophagy context, ATG3 would not be the only protein proposed to sense membrane curvature through an amphipathic helix, Barkor is also involved in detecting this curvature in phosphatidylinositol 3-phosphate (PI3P)-enriched membranes 42,43 . Moreover, there are evidences suggesting that the autophagosome biogenesis is a lipid-modulated process 44 . While the role of phosphoinositides (PI3P, PI4P, PI5P, PI(4,5)P 2 ) in autophagy progression is well known [44][45][46] , little information on the participation of other lipid species during the different steps of autophagosome biogenesis has been reported 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Human ATG3 Binding to Lipid Bilayers. Role of Lipid Geometry and Electric Charge

Hervás

Landajuela

Antón

et al. 2018

Biophysical Journal

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Specific protein-lipid interactions lead to a gradual recruitment of AuTophaGy-related (ATG) proteins to the nascent membrane during autophagosome (AP) formation. ATG3, a key protein in the movement of LC3 towards the isolation membrane, has been proposed to facilitate LC3/GABARAP lipidation in highly curved membranes. In this work we have performed a biophysical study of human ATG3 interaction with membranes containing phosphatidylethanolamine, phosphatidylcholine and anionic phospholipids. We have found that ATG3 interacts more strongly with negatively-charged phospholipid vesicles or nanotubes than with electrically neutral model membranes, cone-shaped anionic phospholipids (cardiolipin and phosphatidic acid) being particularly active in promoting binding. Moreover, an increase in membrane curvature facilitates ATG3 recruitment to membranes although addition of anionic lipid molecules makes the curvature factor relatively less important. The predicted N-terminus amphipathic α-helix of ATG3 would be responsible for membrane curvature detection, the positive residues Lys 9 and 11 being essential in the recognition of phospholipid negative moieties. We have also observed membrane aggregation induced by ATG3 in vitro, which could point to a more complex function of this protein in AP biogenesis. Moreover, in vitro GABARAP lipidation assays suggest that ATG3-membrane interaction could facilitate the lipidation of ATG8 homologues.Macroautophagy is a bulk degradation pathway conserved among eukaryotic cells 1 . This process is characterized by the generation of a double membrane structure called autophagosome (AP) which engulfs organelles or cytoplasmic portions and subsequently delivers the material into the lysosome for degradation 2 . AP formation requires more than 30 autophagy-related (ATG) proteins acting in a hierarchical way 3 . Among these proteins an ubiquitin-like (UBL) system, composed by Atg7, Atg3 and Atg8, triggers the covalent attachment of Atg8 (LC3 and GABARAP subfamilies in mammals) to phosphatidylethanolamine (PE), a lipid found in the AP membrane 4,5 . It has been shown that Atg3 is responsible for transferring Atg8 to the membrane 6,7 , where Atg8 participates in AP formation, maturation and closure. In fact, it has been described that mammalian Atg8-like proteins (LC3, GATE-16 and GABARAP) induce membrane tethering and fusion in vitro [8][9][10] , which could be related to the AP growth process. The correct equilibrium of these processes is vital for the maintenance of cell homeostasis, and their imbalance is related to human disorders e.g. neurodegenerative diseases and cancer.Human ATG3, the E2-like enzyme for Atg8 conjugation, contains some disordered regions that allow its classification among the intrinsically disordered proteins 11 . This property is found in proteins that participate in processes required for quick cellular responses, such as autophagy. Atg3 handle region (HR) and flexible region (FR) have been found to interact with Atg7 and Atg8, respectively 12 . These two domains ac...

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The Role of Lipids in the Control of Autophagy

Cited by 253 publications

References 128 publications

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

Human ATG3 Binding to Lipid Bilayers. Role of Lipid Geometry and Electric Charge

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