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Autophagic flux and autophagosome morphogenesis require the participation of sphingolipids

  • THE ROLE OF SPHINGOLIPIDS AND LIPID RAFTS IN DETERMINING CELL FATE
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Abstract

Apoptosis and autophagy are two evolutionary conserved processes that exert a critical role in the maintenance of tissue homeostasis. While apoptosis is a tightly regulated cell program implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in the lysosomal degradation and recycling of proteins and organelles, and is thereby considered an important cytoprotection mechanism. Sphingolipids (SLs), which are ubiquitous membrane lipids in eukaryotes, participate in the generation of various membrane structures, including lipid rafts and caveolae, and contribute to a number of cellular functions such as cell proliferation, apoptosis and, as suggested more recently, autophagy. For instance, SLs are hypothesized to be involved in several intracellular processes, including organelle membrane scrambling, whilst at the plasma membrane lipid rafts, acting as catalytic domains, strongly contribute to the ignition of critical signaling pathways determining cell fate. In particular, by targeting several shared regulators, ceramide, sphingosine-1-phosphate, dihydroceramide, sphingomyelin and gangliosides seem able to differentially regulate the autophagic pathway and/or contribute to the autophagosome formation. This review illustrates recent studies on this matter, particularly lipid rafts, briefly underscoring the possible implication of SLs and their alterations in the autophagy disturbances and in the pathogenesis of some human diseases.

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Abbreviations

AMP:

Adenosine monophosphate

AMPK:

AMP kinase

ATG:

Autophagy-related gene

ATP:

Adenosine triphosphate

Bax:

BCL2-associated X protein

Bcl-2:

B cell lymphoma 2

BH3:

Bcl-2 homology domain 3

Bnip3:

Bcl-2/adenovirus E1B nineteen kilodalton interacting protein 3

CDases:

Ceramidases

Cer:

Ceramide

CerS:

Ceramide synthase

CERT:

Cer, transfer protein

CMA:

Chaperone-mediated autophagy

DES:

Dihydroceramide desaturase

dhCer:

Dihydroceramide

dhCerS:

Dihydroceramide synthase

DR:

Death receptor

DRAM:

Damage-regulated autophagy modulator

EGFR:

Epidermal growth factor receptor

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

FAPP2:

Four-phosphate adaptor protein 2

FLIP:

FLICE inhibitor protein

GCase:

Glucocerebrosidase

GCS:

Glucosylceramide synthase

GD:

Gaucher disease

IKBKB:

IκB kinase β

IKK:

Inhibitor of kappa B kinase

IL-1:

Interleukin-1

JNK:

Jun N-terminal kinase

LAMP1:

Lysosomal-associated membrane protein 1

LC3:

Microtubule-associated protein light chain 3

LDL:

Low density lipoprotein

MAMs:

Mitochondria-associated membranes

MAPK:

Mitogen activated protein kinase

MMP:

Mitochondrial membrane permeability

Mtor:

Mechanistic target of rapamycin

NF-kB:

Nuclear factor kappa B

NPC:

Niemann–Pick disease type C

PE:

Phosphatidyl-ethanolamine

PI3K/AKT:

Phosphatidylinositol-3-kinases/AKT

PtdIns(3)P:

Phosphatidylinositol 3-phospate

ROS:

Reactive oxygen species

S1P:

Sphingosine-1-phosphate

S1P lyase:

Sphingosine-1-phosphate lyase

Sap C:

Saposin C

SLs:

Sphingolipids

SM:

Sphingomyelin

SMases:

Sphingomyelinases

SMS:

Sphingomyelin synthase

SphKs:

Sphingosine kinases

SPPs:

Sphingosine-1-phosphate phosphatases

THC:

Cannabinoid tetrahydrocannabinol

TNF-α:

Tumor necrosis factor-α

TRAIL:

Tumor necrosis factor-alpha-related apoptosis-inducing ligand

ULK1:

Unc-51-like kinase 1

UV:

Ultraviolet

UVRAG:

Activating molecule in Beclin-1 regulated autophagy

VEGFR:

Vascular endothelial growth factor receptor

Vps:

Vacuolar protein sorting

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Acknowledgments

Partially supported by Peretti Foundation, Arcobaleno Onlus and AIRC.

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    Authors and Affiliations

    1. Section of Cell Aging and Degeneration, Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

      Chiara Tommasino, Matteo Marconi, Laura Ciarlo, Paola Matarrese & Walter Malorni

    2. Center of Integrated Metabolomics, Rome, Italy

      Paola Matarrese

    3. San Raffaele Pisana Institute, Rome, Italy

      Walter Malorni

    4. Section of Cell Aging, Degeneration and Gender Medicine, Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

      Paola Matarrese

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    1. Chiara Tommasino
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    2. Matteo Marconi
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    3. Laura Ciarlo
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    4. Paola Matarrese
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    5. Walter Malorni
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    Correspondence to Paola Matarrese or Walter Malorni.

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    Chiara Tommasino and Matteo Marconi to be considered as first authors.

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    Tommasino, C., Marconi, M., Ciarlo, L. et al. Autophagic flux and autophagosome morphogenesis require the participation of sphingolipids. Apoptosis 20, 645–657 (2015). https://doi.org/10.1007/s10495-015-1102-8

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