Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation
- 1Indian Institute of Science Education and Research (IISER) Pune
Abstract
Phagocytosis, a central process in innate immunity, depends on dynamic lipid remodelling, yet how cholesterol accumulates on late phagosomes remains unresolved. Here, we identify lysosomal acid lipase (LIPA) as a key cholesterol ester (CE) hydrolase driving cholesterol mobilization during phagosomal maturation. Using integrated lipidomics, chemoproteomics, and biochemical assays, we show that LIPA exhibits acidic CE hydrolase activity enriched on late phagosomes, generating free cholesterol essential for lipid raft formation. Pharmacologically inhibiting LIPA disrupts cholesterol-rich lipid raft assembly, impairs phagosomal trafficking, and alters pathogen fate - enhancing Staphylococcus aureus persistence, while restricting Mycobacterium tuberculosis survival. These findings reveal that LIPA couples cholesterol metabolism to phagocytosis, defining a mechanistic link between lipid catabolism and antimicrobial defence. By positioning CE hydrolysis as a critical determinant of phagosomal dynamics, our work uncovers a metabolic checkpoint in innate immunity and identifies LIPA as a potential therapeutic node in infection and inflammation.
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BibTeX
@misc{saharan2026lysosomal,
title = {{Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation}},
author = {O. Saharan and B. Bhawna and S. S. K. Saraswati and A. Akhir and S. Chopra and D. Kumar and R. Mallik and S. Kamat},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752819},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752819v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation
AU - O. Saharan
AU - B. Bhawna
AU - S. S. K. Saraswati
AU - A. Akhir
AU - S. Chopra
AU - D. Kumar
AU - R. Mallik
AU - S. Kamat
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752819
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752819v1
AB - Phagocytosis, a central process in innate immunity, depends on dynamic lipid remodelling, yet how cholesterol accumulates on late phagosomes remains unresolved. Here, we identify lysosomal acid lipase (LIPA) as a key cholesterol ester (CE) hydrolase driving cholesterol mobilization during phagosomal maturation. Using integrated lipidomics, chemoproteomics, and biochemical assays, we show that LIPA exhibits acidic CE hydrolase activity enriched on late phagosomes, generating free cholesterol essential for lipid raft formation. Pharmacologically inhibiting LIPA disrupts cholesterol-rich lipid raft assembly, impairs phagosomal trafficking, and alters pathogen fate - enhancing Staphylococcus aureus persistence, while restricting Mycobacterium tuberculosis survival. These findings reveal that LIPA couples cholesterol metabolism to phagocytosis, defining a mechanistic link between lipid catabolism and antimicrobial defence. By positioning CE hydrolysis as a critical determinant of phagosomal dynamics, our work uncovers a metabolic checkpoint in innate immunity and identifies LIPA as a potential therapeutic node in infection and inflammation.
ER -