Journal Articles Autophagy Year : 2024

Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death

Karla Alvarez-Valadez
Allan Sauvat
Julien Diharce
Marion Leduc
  • Function : Author
Gautier Stoll
Lionel Guittat
Flavia Lambertucci
Juliette Paillet
Omar Motiño
Lucille Ferret
  • Function : Author
Alexandra Muller
  • Function : Author
Sabrina Forveille
  • Function : Author
Maria Chiara Maiuri
Oliver Kepp
Harald Wodrich

Abstract

Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.
Fichier principal
Vignette du fichier
Manuscript text.pdf (505) Télécharger le fichier
Figures.pdf (44) Télécharger le fichier
Origin Files produced by the author(s)
Origin Files produced by the author(s)

Dates and versions

hal-04875040 , version 1 (08-01-2025)

Identifiers

Cite

Karla Alvarez-Valadez, Allan Sauvat, Julien Diharce, Marion Leduc, Gautier Stoll, et al.. Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death. Autophagy, 2024, 08, pp.1-23. ⟨10.1080/15548627.2024.2440842⟩. ⟨hal-04875040⟩
12 View
0 Download

Altmetric

Share

More