Lysosomal degradation of membrane lipids

Kolter, Thomas; Sandhoff, Konrad

doi:10.1016/j.febslet.2009.10.021

Cited by 250 publications

(227 citation statements)

References 214 publications

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“…Finally, LBPA is a poor substrate for lipases and phospholipases, which has led to the notion that it may be the stereoisomer of other naturally occurring phospholipids (Brotherus et al 1974;Joutti 1979;Thornburg et al 1991;Chevallier et al 2000), as was recently shown (Tan et al 2012). This notion is consistent with observations that LBPA facilitates the degradation of glycosphingolipids in vitro by enhancing the lipid-extraction capacity of saposins (Kolter and Sandhoff 2010). LBPA may also facilitate HSP70 entry into lysosomes and lysosome stabilization (Kirkegaard et al 2010).…”

Section: Restricted Lipid Localization Via Spatially Controlled Synthsupporting

confidence: 77%

Lipid Sorting and Multivesicular Endosome Biogenesis

Bissig

Grüenberg

2013

Cold Spring Harbor Perspectives in Biology

133

107

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Intracellular organelles, including endosomes, show differences not only in protein but also in lipid composition. It is becoming clear from the work of many laboratories that the mechanisms necessary to achieve such lipid segregation can operate at very different levels, including the membrane biophysical properties, the interactions with other lipids and proteins, and the turnover rates or distribution of metabolic enzymes. In turn, lipids can directly influence the organelle membrane properties by changing biophysical parameters and by recruiting partner effector proteins involved in protein sorting and membrane dynamics. In this review, we will discuss how lipids are sorted in endosomal membranes and how they impact on endosome functions.

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Section: Restricted Lipid Localization Via Spatially Controlled Synthsupporting

confidence: 77%

Lipid Sorting and Multivesicular Endosome Biogenesis

Bissig

Grüenberg

2013

Cold Spring Harbor Perspectives in Biology

133

107

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“…These findings support a mechanism in which SapC inserts directly into the lipid bilayer, thereby disrupting the tightly packed lipids that comprise the target membrane. These SapC-liposome interactions are reminiscent of SapC-membrane interactions observed in the context of glycosphingolipid (GSL) degradation whereby SapC inserts into membrane bilayers to provide lysosomal hydrolases greater accessibility to GSL substrates embedded in model membranes (19)(20)(21)(22). Because membraneassociated SapC facilitates GSL degradation by positioning hydrolytic enzymes, such as β-glucosidase, next to disorganized membrane environments where GSL substrates are accessible (23,24), we tested whether SapC also interacts with CD1 molecules on the surface of model membranes.…”

Section: Resultsmentioning

confidence: 99%

Saposins utilize two strategies for lipid transfer and CD1 antigen presentation

León

Tatituri

Grenha

et al. 2012

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

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Transferring lipid antigens from membranes into CD1 antigenpresenting proteins represents a major molecular hurdle necessary for T-cell recognition. Saposins facilitate this process, but the mechanisms used are not well understood. We found that saposin B forms soluble saposin protein-lipid complexes detected by native gel electrophoresis that can directly load CD1 proteins. Because saposin B must bind lipids directly to function, we found it could not accommodate long acyl chain containing lipids. In contrast, saposin C facilitates CD1 lipid loading in a different way. It uses a stable, membrane-associated topology and was capable of loading lipid antigens without forming soluble saposin-lipid antigen complexes. These findings reveal how saposins use different strategies to facilitate transfer of structurally diverse lipid antigens. . Although the molecular mechanisms governing MHC class I and II peptide loading are well appreciated, the mechanisms of CD1 lipid loading remain poorly understood. In the case of MHC class I molecules, proteasome-derived peptides are loaded onto MHC class I molecules by proteins of the peptide loading complex whose components include calnexin, calreticulin, ERp57, tapasin, and TAP (2). MHC class II molecules are loaded in endosomal compartments, where HLA-DM facilitates the exchange of the class II associated invariant peptide for high-affinity peptides derived from lysosomal processing of exogenous proteins (3, 4). The capacity of the MHC class I and II processing and antigen loading mechanisms are major factors determining which peptides are antigenic. In contrast to MHC-presented peptides, CD1-restricted lipid antigens are amphipathic molecules that are typically embedded in cellular membranes or micelles (5) and thus may be largely inaccessible to luminal proteins. Given the nonpolar component of lipids, mobilization of membrane-derived lipids across an aqueous endocytic environment likely requires extraction from membranes and, in most cases, transport across aqueous biological buffers into the lipid-binding grooves of CD1 molecules. These related processes are predicted to have unfavorable dissolution energetics and is unlikely to occur efficiently without the assistance of lipid-transfer proteins or other molecular mediators (6, 7).Recent studies have shown that saposins, a family of small, nonenzymatic lipid-binding proteins, facilitate CD1 lipid loading in endosomal compartments (6,(8)(9)(10). To a relative extent, all saposins enhance CD1 lipid loading in cellular and in vitro assays, but they appear to have a differential capacity to load particular lipids into individual CD1 isoforms. In one study, saposin B (SapB) was shown to facilitate α-galactosylceramide (αGalCer) loading onto human CD1d molecules more efficiently than other saposin isoforms (9). In cellular studies, saposin C (SapC), but not other saposins, restored CD1b presentation of long-chain mycobacterial antigens in saposin-deficient antigen presenting cells (8). Furthermore, direct visualization of lipid-l...

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“…FRET efficiency (E) can be determined from the Figure 7 | Current model for regulation of exosomal MVE maturation by a receptor-mediated S1P signalling. During MVE maturation the lipid composition of ILV membrane dramatically changes, that is, the level of ceramide increases at the expense of sphingomyelin, which is rapidly degraded by various sphingomyelinases 65 . Ceramide is sequentially metabolized to S1P by SphK2 via sphingosine.…”

Section: Methodsmentioning

confidence: 99%

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

et al. 2013

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During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomes for degradation or fused with the plasma membranes for exosome release. The mechanism underlying formation of exosomal ILVs and cargo sorting into ILVs destined for exosome release is still unclear. Here we show that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation. Gi-coupled S1P receptors on MVEs are constitutively activated through a constant supply of S1P via autocrine activation within organelles. We also found that the continuous activation of Gi-coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release. Our results reveal a mechanism underlying ESCRT-independent maturation of exosomal MVEs.

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Lysosomal degradation of membrane lipids

Cited by 250 publications

References 214 publications

Lipid Sorting and Multivesicular Endosome Biogenesis

Lipid Sorting and Multivesicular Endosome Biogenesis

Saposins utilize two strategies for lipid transfer and CD1 antigen presentation

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

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