ArticleThe Journal of biological chemistry2011
A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement for carboxyl-terminal proteolytic processing.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 60 citations in OpenAlex.
- Phospholipids, Sphingolipids, and Cholesterol-Derived Lipid Mediators and Their Role in Neurological Disorders.International journal of molecular sciences · 2024Review
- Schlank orchestrates insect developmental transition by switching H3K27 acetylation to trimethylation in the prothoracic gland.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Ceramide-mediated orchestration of oxidative stress response through filopodia-derived small extracellular vesicles.Journal of extracellular vesicles · 2024Article
- MicroRNA-10a enrichment in factor VIIa-released endothelial extracellular vesicles: potential mechanisms.Journal of thrombosis and haemostasis : JTH · 2024Article
- The relevance of acid sphingomyelinase as a potential target for therapeutic intervention in hepatic disorders: current scenario and anticipated trends.Archives of toxicology · 2023Review
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- Mechanistic analysis and significance of sphingomyelinase-mediated decreases in transepithelial CFTR currents in nHBEs.Physiological reports · 2021Article
- Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism.International journal of molecular sciences · 2021Review
- The doxorubicin-induced cell motility network is under the control of the ceramide-activated protein phosphatase 1 alpha.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Solving the secretory acid sphingomyelinase puzzle: Insights from lysosome-mediated parasite invasion and plasma membrane repair.Cellular microbiology · 2019Review
- Acid Sphingomyelinase regulates the localization and trafficking of palmitoylated proteins.Biology open · 2019Article
- Plasma membrane damage repair is mediated by an acid sphingomyelinase in Entamoeba histolytica.PLoS pathogens · 2019Article
- Approaches for probing and evaluating mammalian sphingolipid metabolism.Analytical biochemistry · 2019Review
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- Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury.Journal of lipid research · 2019Article
- Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis.Journal of lipid research · 2018Article
- Acid sphingomyelinase is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells.Journal of cell science · 2016Article
- Keratin impact on PKCδ- and ASMase-mediated regulation of hepatocyte lipid raft size - implication for FasR-associated apoptosis.Journal of cell science · 2016Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Acid sphingomyelinase (aSMase) catalyzes the hydrolysis of sphingomyelin (SM) to form the bioactive lipid ceramide (Cer). Notably, aSMase exists in two forms: a zinc (Zn(2+))-independent lysosomal aSMase (L-SMase) and a Zn(2+)-dependent secreted aSMase (S-SMase) that arise from alternative trafficking of a single protein precursor. Despite extensive investigation into the maturation and trafficking of aSMase, the exact identity of mature L-SMase has remained unclear. Here, we describe a novel mechanism of aSMase maturation involving C-terminal proteolytic processing within, or in close proximity to, endolysosomes. Using two different C-terminal-tagged constructs of aSMase (V5, DsRed), we demonstrate that aSMase is processed from a 75-kDa, Zn(2+)-activated proenzyme to a mature 65 kDa, Zn(2+)-independent L-SMase. L-SMase is recognized by a polyclonal Ab to aSMase, but not by anti-V5 or anti-DsRed antibodies, suggesting that the C-terminal tag is lost during maturation. Furthermore, indirect immunofluorescence staining demonstrated that mature L-SMase colocalized with the lysosomal marker LAMP1, whereas V5-aSMase localized to the Golgi secretory pathway. Moreover, V5-aSMase possessed Zn(2+)-dependent activity suggesting it may represent the common protein precursor of S-SMase and L-SMase. Importantly, the 65-kDa L-SMase, but not V5-aSMase, was sensitive to the lysosomotropic inhibitor desipramine, co-fractionated with lysosomes, and migrated at the same M(r) as partially purified human aSMase. Finally, three aSMase mutants containing C-terminal Niemann-Pick mutations (R600H, R600P, ΔR608) exhibited defective proteolytic maturation. Taken together, these results demonstrate that mature L-SMase arises from C-terminal proteolytic processing of pro-aSMase and suggest that impaired C-terminal proteolysis may lead to severe defects in L-SMase function.
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