Journal
CELL DEATH & DISEASE
Volume 11, Issue 5, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-020-2556-3
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Funding
- Inserm, Universite de Lille, CHU de Lille
- Ligue Nationale contre le Cancer, comite de la Somme
- comite du Nord
- Initiatives d'excellence [ANR-11-LABX-0071, Idex ANR-11-IDEX-0005-02]
- Groupama Foundation - Research Prize for Rare Diseases
- Human Frontier Science Program [RGP0038/2018]
- Contrat de Plan Etat Region (CPER Cancer 2007-2013)
- ANR [ANR-10-LABX-46, ANR-10-EQPX-07-01]
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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.
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