PRINCIPLES OF LYSOSOMAL MEMBRANE DIGESTION: Stimulation of Sphingolipid Degradation by Sphingolipid Activator Proteins and Anionic Lysosomal Lipids
Abstract
Sphingolipids and glycosphingolipids are membrane components of eukaryotic cell surfaces. Their constitutive degradation takes place on the surface of intra-endosomal and intra-lysosomal membrane structures. During endocytosis, these intra-lysosomal membranes are formed and prepared for digestion by a lipid-sorting process during which their cholesterol content decreases and the concentration of the negatively charged bis(monoacylglycero)phosphate (BMP)—erroneously also called lysobisphosphatidic acid (LBPA)—increases. Glycosphingolipid degradation requires the presence of water-soluble acid exohydrolases, sphingolipid activator proteins, and anionic phospholipids like BMP. The lysosomal degradation of sphingolipids with short hydrophilic head groups requires the presence of sphingolipid activator proteins (SAPs). These are the saposins (Saps) and the GM2 activator protein. Sphingolipid activator proteins are membrane-perturbing and lipid-binding proteins with different specificities for the bound lipid and the activated enzyme-catalyzed reaction. Their inherited deficiency leads to sphingolipid- and membrane-storage diseases. Sphingolipid activator proteins not only facilitate glycolipid digestion but also act as glycolipid transfer proteins facilitating the association of lipid antigens with immunoreceptors of the CD1 family.
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The associated childhood disorders highlight the variety of processes in which the lysosome is involved, from myelination (TMEM106B, hypomyelinating leukodystrophy) to cell growth (TSC1, tuberous sclerosis) and bone resorption (SQSTM1).
“The associated childhood disorders highlight the variety of processes in which the lysosome is involved, from myelination (TMEM106B, hypomyelinating leukodystrophy) to cell growth (TSC1, tuberous sclerosis) and bone resorption (SQSTM1).89–91”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [89]
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- Authors
- Kolter, T., & Sandhoff, K.
- Affiliations
- University of Bonn (DE)
- Venue
- Annual Review of Cell and Developmental Biology
- Publisher
- Annual Reviews
- Published
- 2005-11-01
- Volume
- 21
- Issue
- 1
- Pages
- 81-103
- ISSN
- 1081-0706 (ISSN-L)
- 1530-8995
- OpenAlex
- W2125738893
- Cited by
- 464
- References
- 3
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 29 · 2023: 16 · 2022: 18 · 2021: 24 · 2020: 16 · 2019: 15 · 2018: 26 · 2017: 13 · 2016: 20 · 2015: 18 · 2014: 23 · 2013: 20 · 2012: 17
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Cell and Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- sphingolipid degradation, sphingolipid activator proteins, saposins, GM2 activator protein, bis(monoacylglycero)phosphate, endocytosis, lipid sorting, glycolipid transfer protein
- MeSH terms
- Animals, Anions, Humans, Intracellular Membranes, Lysosomes, Membrane Lipids, Models, Biological, Sphingolipids, Sphingolipid Activator Proteins
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