Diacylglycerol triggers Rim101 pathway–dependent necrosis in yeast: a model for lipotoxicity

Abstract

The loss of lipid homeostasis can lead to lipid overload and is associated with a variety of disease states. However, little is known as to how the disruption of lipid regulation or lipid overload affects cell survival. In this study we investigated how excess diacylglycerol (DG), a cardinal metabolite suspected to mediate lipotoxicity, compromises the survival of yeast cells. We reveal that increased DG achieved by either genetic manipulation or pharmacological administration of 1,2-dioctanoyl-sn-glycerol (DOG) triggers necrotic cell death. The toxic effects of DG are linked to glucose metabolism and require a functional Rim101 signaling cascade involving the Rim21-dependent sensing complex and the activation of a calpain-like protease. The Rim101 cascade is an established pathway that triggers a transcriptional response to alkaline or lipid stress. We propose that the Rim101 pathway senses DG-induced lipid perturbation and conducts a signaling response that either facilitates cellular adaptation or triggers lipotoxic cell death. Using established models of lipotoxicity, i.e., high-fat diet in Drosophila and palmitic acid administration in cultured human endothelial cells, we present evidence that the core mechanism underlying this calpain-dependent lipotoxic cell death pathway is phylogenetically conserved.

Lipotoxicty in yeast: a focus on plasma membrane signalling and membrane contact sites

“… 2010 ) and most recently by (iv) excess DG (Rockenfeller et al. 2018 ). Whether the adverse effects of lipid overload in the QKO or similar models also depend on Rim101 signalling and whether PM asymmetry is disturbed still remains to be tested.…”

“… 2014 ; Rockenfeller et al. 2018 ), which at first glance seems counterintuitive. A potential explanation for this could be that active Rim101 signalling is needed to efficiently direct lipids from the PM to the ER.…”

“… 2014 ; Rockenfeller et al. 2018 ). These findings raise the possibility that yeast cells may initiate a Rim101-dependent form of necrosis if cells are unable to adapt to lipotoxic conditions.…”

“… 2011 ; Rockenfeller et al. 2018 ). The current model of ceramide toxicity is mostly derived from in vitro models and involves ceramide-induced pore formation in the outer mitochondrial membrane (Birbes et al.…”

Guidelines and recommendations on yeast cell death nomenclature

“…In yeast, necrotic cell death also seems to depend on mitochondria in several settings 149 165 221 . In addition, recent reports show that necrotic cell death upon a lipotoxic insult requires a functional Rim101 signaling cascade that involves the calpain-like protease Rim13/Cpl1 for lethal execution 254 255 . To interrogate a possible case of regulated necrosis, it is thus advisable to evaluate a possible mitochondrial involvement.…”