Small Molecule Screen Reveals Joint Regulation of Stress Granule Formation and Lipid Droplet Biogenesis.

Triana Amen,Daniel Kaganovich

doi:10.3389/fcell.2020.606111

Abstract

Metabolic regulation is a necessary component of all stress response pathways, because all different mechanisms of stress-adaptation place high-energy demands on the cell. Mechanisms that integrate diverse stress response pathways with their metabolic components are therefore of great interest, but few are known. We show that stress granule (SG) formation, a common adaptive response to a variety of stresses, is reciprocally regulated by the pathways inducing lipid droplet accumulation. Inability to upregulate lipid droplets reduces stress granule formation. Stress granule formation in turn drives lipid droplet clustering and fatty acid accumulation. Our findings reveal a novel connection between stress response pathways and new modifiers of stress granule formation.

Highlights

Lipid droplets (LD) are ubiquitous lipid storage organelles that are involved in regulating energy homeostasis and membrane synthesis
To confirm that PABPC1 inclusions are stress granule (SG), we used common SG markers, G3BP and TIA1 (Figure 4D), and independent human cell lines (Supplementary Figure 3E). These data indicate that SG and LD formation are both regulated by the peroxisome proliferator-activated receptor (PPAR) response, which can facilitate SG formation by inhibiting mammalian target of rapamycin (mTOR) kinase, and LD formation can be a consequence of mTOR inhibition (Li et al, 2012) or other unknown pathways (Figure 4E)
Cells activate distinct protective mechanisms such as upregulation of chaperones and protein quality control compartments, synthesis of antioxidant proteins, and increase in LD formation, allowing cells to mitigate the consequences of stress and adapt to stress conditions (Lindquist, 1981; Gingras et al, 1999; Kaganovich et al, 2008; Spriggs et al, 2010)

Summary

INTRODUCTION

Lipid droplets (LD) are ubiquitous lipid storage organelles that are involved in regulating energy homeostasis and membrane synthesis Their importance to the cell has been thought to derive from the need to sequester excess fatty acids, as an energy reserve and to prevent lipotoxicity (Guo et al, 2009; Nguyen and Olzmann, 2017; Walther et al, 2017; Olzmann and Carvalho, 2019). Our study provides evidence of a joint regulation of SG and LD biogenesis

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES