Lysosomal proteome and lipidome analyses of intestinal cells reveal the crucial role of bis(monoacylglycero)phosphate for autophagosome-lysosome fusion
- 1Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel
Abstract
The transport of about 70 enzymes to lysosomes depends on mannose 6-phosphate signals formed by GNPTAB. Editing of Gnptab in an intestinal mouse cell line revealed the loss of multiple lysosomal enzymes associated with the accumulation of sphingomyelins, ceramides, and cholesterol, and reduced levels of bis(monoacylglycero)phosphate (BMP) in lysosomal proteomes and lipidomes. By cross-correlation we identified two subsets of lysosomal lipid-modifying enzymes linked with mixed unsaturated or di-monosaturated BMP. Autophagy-related proteins functioning in early stages of autophagosome formation associated with neutral ceramides, whereas proteins involved in autophagosome-lysosome fusion correlated with negatively charged BMPs. Therefore, the high cholesterol and low BMP level of lysosomes might be causal for impaired autophagic flux in GNPTAB deficient cells. We propose a functional axis of three lysosomal proteins as potential target to improve the autophagic flux in cells with dysfunctional lysosomes and in a newly established intestinal organoid model suitable as novel experimental tool.
Related
- Lysosomal lipidomics identifies glycosylated bis(monoacylglycero)phosphate as a novel biomarker of mutant GBA1
- Autophagosome-tethering compounds selectively lower mutant ataxin-3 in preclinical models of spinocerebellar ataxia type 3
- Sarcoplasmic reticulum remodeling through autophagosome biogenesis during Drosophila metamorphosis
- Ubiquitin ligase RNF126 exerts functions in lysosomal damage response and lysosomal homeostasis maintenance
- Lysosomal Glycosaminoglycan Catabolism Regulates Microglial Cell State in the Developing CNS
BibTeX
@misc{gallo2026lysosomal,
title = {{Lysosomal proteome and lipidome analyses of intestinal cells reveal the crucial role of bis(monoacylglycero)phosphate for autophagosome-lysosome fusion}},
author = {G. Del Gallo and Z. Chen and A. Sanner and R. Hardt and F. Merciai and F. Salsano and S. Bose and M. Schweizer and D. L. Medina and J. B. Bosse and E. M. Sommella and D. Winter and S. Jabs and T. Braulke},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753291},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753291v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Lysosomal proteome and lipidome analyses of intestinal cells reveal the crucial role of bis(monoacylglycero)phosphate for autophagosome-lysosome fusion
AU - G. Del Gallo
AU - Z. Chen
AU - A. Sanner
AU - R. Hardt
AU - F. Merciai
AU - F. Salsano
AU - S. Bose
AU - M. Schweizer
AU - D. L. Medina
AU - J. B. Bosse
AU - E. M. Sommella
AU - D. Winter
AU - S. Jabs
AU - T. Braulke
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753291
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753291v1
AB - The transport of about 70 enzymes to lysosomes depends on mannose 6-phosphate signals formed by GNPTAB. Editing of Gnptab in an intestinal mouse cell line revealed the loss of multiple lysosomal enzymes associated with the accumulation of sphingomyelins, ceramides, and cholesterol, and reduced levels of bis(monoacylglycero)phosphate (BMP) in lysosomal proteomes and lipidomes. By cross-correlation we identified two subsets of lysosomal lipid-modifying enzymes linked with mixed unsaturated or di-monosaturated BMP. Autophagy-related proteins functioning in early stages of autophagosome formation associated with neutral ceramides, whereas proteins involved in autophagosome-lysosome fusion correlated with negatively charged BMPs. Therefore, the high cholesterol and low BMP level of lysosomes might be causal for impaired autophagic flux in GNPTAB deficient cells. We propose a functional axis of three lysosomal proteins as potential target to improve the autophagic flux in cells with dysfunctional lysosomes and in a newly established intestinal organoid model suitable as novel experimental tool.
ER -