BCL-xL antagonizes the deleterious effects of KRAS on mitochondrial scaffolding

Belaid, N.; Basseville, A.; Andre-Gregoire, G.; Fetiveau, A.; Maillet, L.; Guilloneau, F.; Leduc, M.; Guette, C.; Desaubry, L.; Gavard, J.; Gautier, F.; Juin, P.

doi:10.1101/2022.04.13.488211

bioRxiv · 10.1101/2022.04.13.488211

BCL-xL antagonizes the deleterious effects of KRAS on mitochondrial scaffolding

Belaid, N.·Basseville, A.·Andre-Gregoire, G.·Fetiveau, A.·Maillet, L.·Guilloneau, F.·Leduc, M.·Guette, C.·Desaubry, L.·Gavard, J.·Gautier, F.·Juin, P.

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Abstract

In addition to its canonical role as a regulator of mitochondrial outer membrane permeabilization, BCL-xL exerts diverse non canonical functions contributing to cancer cell aggressiveness. In particular it regulates KRAS intracellular activation levels. We herein explored the mechanistic basis for this effect by a spatially restricted biotin-labelling proteomic approach designed to characterize proteins whose proximity to KRAS, used as a bait, is BCL-xL dependant. BCL-xL loss relocalizes KRAS to the vicinity of mitochondrial proteins. Proximal proteins include the mitochondrial scaffold prohibitin 2 (PHB2), which also interacts with BCL-xL and the downregulation of which prevents BCL-xL sensitive effects of KRAS induced contacts between mitochondria and endosomes, and mitochondrial mass decrease. These results argue that BCL-xL prevents a negative feedback regulation of KRAS canonical signaling by KRAS interference with mitochondrial quality control.

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Belaid, N., Basseville, A., Andre-Gregoire, G., Fetiveau, A., Maillet, L., Guilloneau, F., Leduc, M., Guette, C., Desaubry, L., Gavard, J., Gautier, F., Juin, P.. 2022-04-13. BCL-xL antagonizes the deleterious effects of KRAS on mitochondrial scaffolding. https://doi.org/10.1101/2022.04.13.488211

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