1-Deoxysphingolipids cause autophagosome and lysosome accumulation and trigger NLRP3 inflammasome activation
| Autor: | Eicke Latz, Victor Saavedra, Matthew Mangan, Anke Penno, Mario A. Lauterbach, Lars Kuerschner, Christoph Thiele |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Autophagosome Inflammasomes metabolism [NLR Family Pyrin Domain-Containing 3 Protein] metabolism [Lysosomes] doxSA Hereditary sensory and autonomic neuropathy Macrophage HSAN1 drug effects [Lysosomes] innate immunity pharmacology [Sphingolipids] metabolism [Inflammation] metabolism [Autophagosomes] Cell biology drug effects [Inflammasomes] medicine.anatomical_structure metabolism [Fibroblasts] Research Paper drug effects [Autophagy] macrophage Biology crystal drug effects [NLR Family Pyrin Domain-Containing 3 Protein] 03 medical and health sciences lipid ddc:570 Lysosome NLR Family Pyrin Domain-Containing 3 Protein medicine Autophagy Animals Molecular Biology drug effects [Fibroblasts] Inflammation Sphingolipids Innate immune system 030102 biochemistry & molecular biology Autophagosomes Cell Biology Fibroblasts medicine.disease Sphingolipid Mice Inbred C57BL 030104 developmental biology drug effects [Autophagosomes] NLRP3 inflammasome activation Lysosomes metabolism [Inflammasomes] |
| Zdroj: | Autophagy Autophagy 17(8), 1947-1961 (2021). doi:10.1080/15548627.2020.1804677 |
| ISSN: | 1554-8635 |
| DOI: | 10.1080/15548627.2020.1804677 |
| Popis: | 1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids of clinical relevance as they are elevated in plasma of patients suffering from hereditary sensory and autonomic neuropathy (HSAN1) or type 2 diabetes. Their neurotoxicity is described best but they inflict damage to various cell types by an uncertain pathomechanism. Using mouse embryonic fibroblasts and an alkyne analog of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, we here study the impact of deoxySLs on macroautophagy/autophagy, the regulated degradation of dysfunctional or expendable cellular components. We find that deoxySLs induce autophagosome and lysosome accumulation indicative of an increase in autophagic flux. The autophagosomal machinery targets damaged mitochondria that have accumulated N-acylated doxSA metabolites, presumably deoxyceramide and deoxydihydroceramide, and show aberrant swelling and tubule formation. Autophagosomes and lysosomes also interact with cellular lipid aggregates and crystals that occur upon cellular uptake and N-acylation of monomeric doxSA. As crystals entering the lysophagosomal apparatus in phagocytes are known to trigger the NLRP3 inflammasome, we also treated macrophages with doxSA. We demonstrate the activation of the NLRP3 inflammasome by doxSLs, prompting the release of IL1B from primary macrophages. Taken together, our data establish an impact of doxSLs on autophagy and link doxSL pathophysiology to inflammation and the innate immune system. Abbreviations: alkyne-doxSA: (2S,3R)-2-aminooctadec-17yn-3-ol; alkyne-SA: (2S,3R)-2- aminooctadec-17yn-1,3-diol; aSA: alkyne-sphinganine; ASTM-BODIPY: azido-sulfo-tetramethyl-BODIPY; CerS: ceramide synthase; CMR: clonal macrophage reporter; deoxySLs: 1-deoxysphingolipids; dox(DH)Cer: 1-deoxydihydroceramide; doxCer: 1-deoxyceramide; doxSA: 1-deoxysphinganine; FB1: fumonisin B1; HSAN1: hereditary sensory and autonomic neuropathy type 1; LC3: MAP1LC3A and MAP1LC3B; LPS: lipopolysaccharide; MEF: mouse embryonal fibroblasts; MS: mass spectrometry; N(3)635P: azido-STAR635P; N(3)Cy3: azido-cyanine 3; N(3)picCy3: azido-picolylcyanine 3; NLRP3: NOD-like receptor pyrin domain containing protein 3; P4HB: prolyl 4-hydroxylase subunit beta; PINK1: PTEN induced putative kinase 1; PYCARD/ASC: PYD and CARD domain containing; SPTLC1: serine palmitoyltransferase long chain base subunit 1; SQSTM1: sequestosome 1; TLC: thin layer chromatography. |
| Databáze: | OpenAIRE |
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