Biology subjects

Bulfon, D.

Publications and source records attributed to Bulfon, D..

4 recordsLinked to original sources

bioRxiv2026

Acid phospholipase A1 promotes lysosomal membrane catabolism

The molecular mechanisms of lysosomal glycerophospholipid (GPL) catabolism are incompletely understood. Here, we report that acid phospholipase A1 (APLA1), formerly known as palmitoyl-protein thioesterase 2 (PPT2), is required for efficient GPL degradation. Deletion of APLA1 in human cells results in excess accumulation of phospholipids within lysosomes # a pathological condition termed phospholipidosis. APLA1 activity depends on interactions with negatively charged GPLs and is inhibited by phospholipidosis-inducing cationic amphiphilic drugs. Hydrolysis of zwitterionic, but not anionic, GPLs requires co-activation of APLA1 by the lysosome-specific lipid bis(monoacylglycero)phosphate. Upon pharmacological mTORC inhibition, which increases lysosomal GPL turnover, APLA1-deficient cells exhibit massive accumulation of multilamellar membranes in lysosomes and reduced cytosolic triacylglycerol stores. APLA1 acts in concert with lysosomal phospholipase A2 (PLA2G15). Combined APLA1/PLA2G15-deficiency leads to a severe reduction in acid phospholipase A1/A2 activity, thereby exacerbating phospholipidosis. Our observations provide detailed mechanistic insights into lysosomal GPL catabolism, a crucial pathway for maintaining lipid homeostasis.

biochemistry↗

bioRxiv2025

CLN8 enables a non-canonical phospholipid synthesis pathway

According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol (GPG), resulting in the formation of lysophosphatidylglycerol (LPG). The acyltransferase reaction is catalyzed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived LPG is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis, but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize GPG for BMP synthesis, resulting in BMP-deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP-deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.

biochemistry↗

bioRxiv2025

The Lipid Hydrolase ABHD6 is a Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Related Hepatocellular Carcinoma

Primary liver cancer accounts for approximately 700,000 deaths worldwide annually ranking third in cancer-related mortality, with hepatocellular carcinoma (HCC) comprising the majority of these tumors. Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a leading cause of HCC in the United States. We previously identified the lipid hydrolase alpha/beta hydrolase domain 6 (ABHD6) as a key mediator of the development of metabolic syndrome and intimately involved in cell signaling, making it a prime target for investigation in MASLD-related HCC. ABHD6 displays higher expression within HCC tumor cores when compared to adjacent non-tumor liver tissue in human subjects. Using an in vivo antisense oligonucleotide (ASO)-driven knockdown approach, we have shown the inhibition of ABHD6 prevents the development and progression of HCC in an obesity/MASLD-driven mouse model. Additionally, a xenograft model using the human Huh7 cell line displayed reduced tumor engraftment and growth with ABHD6 genetic deletion and small molecule inhibition. ABHD6 knockout cells demonstrated increased levels of bis(monoacylglycerol)phosphates (BMPs), lipids relevant to high fat diet-induced lysosomal dysfunction, and knockout cells also demonstrated altered autophagy and lysosomal activity using in vitro model of saturated fatty acid-induced lipotoxicity. These studies reveal novel lipid signaling mechanisms by which MASLD progresses towards HCC and provide support for ABHD6 as a therapeutic target in HCC. SignificanceWe have identified that alpha/beta hydrolase domain 6 (ABHD6) plays a role in lysosomal membrane lipid remodeling pathways that are relevant in obesity/MASLD-driven HCC. Inhibitors targeting ABHD6 reorganize lysosomal lipid homeostasis to improve outcomes in HCC.

cancer biology↗

bioRxiv2024

The endolysosomal phospholipid bis(monoacylglycero)phosphate is synthesized via intra- and extracellular pathways

Bis(monoacylglycero)phosphate (BMP) is a major phospholipid constituent of intralumenal membranes in late endosomes/lysosomes, where it regulates the degradation and sorting of lipid cargo. Recent observations suggest that the Batten disease - associated protein CLN5 functions as lysosomal BMP synthase. Here, we show that transacylation reactions catalyzed by cytosolic and secreted enzymes enhance BMP synthesis independently of CLN5. The transacylases identified in this study are capable of acylating the precursor lipid phosphatidylglycerol (PG), generating acyl-PG, which is subsequently hydrolyzed to BMP. Extracellularly, acyl-PG and BMP are generated by endothelial lipase in cooperation with other serum enzymes of the pancreatic lipase family. The intracellular acylation of PG is catalyzed by several members of the cytosolic phospholipase A2 group IV (PLA2G4) family. Overexpression of secreted or cytosolic transacylases was sufficient to correct BMP deficiency in HEK293 cells lacking CLN5. Collectively, our observations suggest that functionally overlapping pathways promote BMP synthesis in mammalian cells.

biochemistry↗