The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues

Medoh, Uche N.; Abu-Remaileh, Monther

doi:10.1146/annurev-biochem-092823-113814

Cited by 3 publications

(7 citation statements)

References 111 publications

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“…Importantly, we found that genetic depletion of PLA2G15 strongly ameliorates neurodegeneration and liver damage leading to increased survival of NPC1-deficient mouse model [44][45][46][47] . These data suggest that inhibiting PLA2G15 represents a potential therapeutic strategy to boost BMP levels and treat multiple lysosome-related diseases, an observation consistent with the BMP therapeutic hypothesis 1 .…”

Section: Discussionsupporting

confidence: 70%

“…We speculate that BMP stability is maintained by an unidentified biological machinery that protects its 2,2' BMP isoform from acyl migration 1 . Future studies should investigate the preferential synthesis or preservation of 2,2' BMP, as well as the enzymes or processes required for its conversion to the 3,3' isoform during its catabolism.…”

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

“…BMP is a unique lipid known to potently stimulate lysosome-mediated lipid turnover, a crucial cellular process, that when defective leads to a plethora of human diseases including neurodegeneration 1,4 . Despite the therapeutic potential in targeting the BMP pathway and its significant functions in the lysosome little is known about BMP synthesis and degradation 1,4 . We have recently discovered CLN5 as a BMP synthase in the lysosome, however, the rules that govern BMP stability and the enzymes that mediate its hydrolysis, if any, are yet to be discovered.…”

Section: Discussionmentioning

confidence: 99%

“…Lysosomes are vital for cellular waste removal, nutrient recycling, and maintaining homeostasis, particularly through breaking down complex lipids using hydrolytic enzymes. Lipid degradation within lysosomes is facilitated by intralysosomal vesicles (ILVs) rich in a unique lipid called bis(monoacylglycero)phosphate (BMP) 1 . BMP significantly enhances lysosomal lipid metabolism, and its imbalance is a hallmark of various lysosome-associated diseases, including age-related neurodegeneration, viral infection, cancer, and atherosclerotic cardiovascular disease [1][2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

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PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease

Nyame,

Xiong,

de Jong

et al. 2024

Preprint

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Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles (ILVs) and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. Although BMP synthase was recently discovered, it has long been thought that BMP’s unique stereochemistry confers resistance to acid phospholipases, a requirement for its role in the lysosome. Here, we demonstrate that PLA2G15, a major lysosomal phospholipase, efficiently hydrolyzes BMP with primary esters regardless of stereochemistry. Interestingly, we discover that BMP’s unique esterification position is what confers resistance to hydrolysis. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates. Conversely, BMP with secondary esters is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient tissues and cells accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. Increasing BMP levels by targeting PLA2G15 reverses the cholesterol accumulation phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorate disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and as a potential target for modulating BMP levels for therapeutic intervention.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease

Nyame,

Xiong,

de Jong

et al. 2024

Preprint

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Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder

Ghoochani,

Heiby,

Rawat

et al. 2024

Preprint

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Mutations in lysosomal genes cause neurodegeneration and neurological lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood. Here, we report a quantitative protein atlas of the lysosome from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of novel lysosomal proteins and reveal the diversity of the lysosomal composition across brain cell types. Notably, we discovered SLC45A1, mutations in which cause a monogenic neurological disease, as a neuron-specific lysosomal protein. Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. Mechanistically, SLC45A1 plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. SLC45A1 deficiency depletes the V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as a LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution in the brain and its implications for neurodegeneration.

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Manipulation of Host Cholesterol by SARS-CoV-2

Doyle,

Goodson,

Kolaczkowski

et al. 2024

Preprint

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SARS-CoV-2 infection is associated with alterations in host lipid metabolism, including disruptions in cholesterol homeostasis, yet the specific mechanisms by which viral proteins influence cholesterol remain incompletely understood. Here, we report that SARS-CoV-2 infection induces cholesterol sequestration within lysosomes, with the viral protein ORF3a identified as the primary driver. ORF3a interacts directly with the HOPS complex subunit VPS39 through a hydrophobic interface formed by residues W193 and Y184, with a W193A mutation significantly rescuing cholesterol egress and correcting the mislocalization of the lysosomal cholesterol transporter NPC2 caused by defective trafficking of the trans-Golgi network (TGN) sorting receptor, the cation-independent mannose-6-phosphate receptor (CI-MPR). We further observed a marked reduction in bis(monoacylglycero)phosphate (BMP), a lipid essential for lysosomal cholesterol export, in both SARS-CoV-2-infected cells and ORF3a-expressing cells. Similar BMP reductions were observed in cells deficient in the HOPS subunits VPS39 and VPS41, but not in VPS29-deficient retromer complex cells, suggesting that BMP reduction is independent of general lysosomal protein trafficking. Inhibition of lysosomal cholesterol egress using the compound U18666A significantly decreased SARS-CoV-2 infection, highlighting a potential viral strategy of manipulating lysosomal cholesterol to modulate host cell susceptibility. Our findings reveal that SARS-CoV-2 ORF3a disrupts cellular cholesterol transport by altering lysosomal protein trafficking and BMP levels, providing new insights into virus-host interactions that contribute to lipid dysregulation in infected cells.

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The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues

Cited by 3 publications

References 111 publications

PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease

PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease

Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder

Manipulation of Host Cholesterol by SARS-CoV-2

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