Galectin-3 modulates epithelial cell adaptation to stress at the ER-mitochondria interface

Published: 12 May 2020 https://doi.org/10.1038/s41419-020-2556-3

Cellular stress response contributes to epithelial defense in adaptation to environment changes. Galectins play a pivotal role in the regulation of this response in malignant cells. However, precise underlying mechanisms are largely unknown. Here we demonstrate that Galectin-3, a pro and anti-apoptotic lectin, is required for setting up a correct cellular response to stress by orchestrating several effects. First, Galectin-3 constitutes a key post-transcriptional regulator of stress-related mRNA regulons coordinating the cell metabolism, the mTORC1 complex or the unfolded protein response (UPR). Moreover, we demonstrated the presence of Galectin-3 with mitochondria-associated membranes (MAM), and its interaction with proteins located at the ER or mitochondrial membranes. There Galectin-3 prevents the activation and recruitment at the mitochondria of the regulator of mitochondria fission DRP-1. Accordingly, loss of Galectin-3 impairs mitochondrial morphology, with more fragmented and round mitochondria, and dynamics both in normal and cancer epithelial cells in basal conditions. Importantly, Galectin-3 deficient cells also display changes of the activity of the mitochondrial respiratory chain complexes, of the mTORC1/S6RP/4EBP1 translation pathway and reactive oxygen species levels. Regarding the ER, Galectin-3 did not modify the activities of the 3 branches of the UPR in basal conditions. However, Galectin-3 favours an adaptative UPR following ER stress induction by Thapsigargin treatment. Altogether, at the ER-mitochondria interface, Galectin-3 coordinates the functioning of the ER and mitochondria, preserves the integrity of mitochondrial network and modulates the ER stress response.

Lucie Coppin, Arnaud Jannin, Emilie Ait Yahya, Caroline Thuillier, Céline Villenet, Meryem Tardivel, Antonino Bongiovanni, Cécile Gaston, Simon de Beco, Nicolas Barois, Isabelle van Seuningen, Emmanuelle Durand, Amélie Bonnefond, Jean-Claude Vienne, Joseph Vamecq, Martin Figeac, Audrey Vincent, Delphine Delacour, Nicole Porchet & Pascal Pigny

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