Lipid droplets and autophagosomes together with chaperones fine‐tune expression of SGK1

Serum‐glucocorticoid‐induced kinase‐1 (SGK1) regulates ion homeostasis and promotes survival under stress conditions. The expression of SGK1 is under transcriptional and post‐translational regulations that are frequently altered in cancer and immune disorders. We report that an N‐terminal amphipathic alpha‐helix determines SGK1 expression levels through two distinct mechanisms. It tethers SGK1 to intracellular organelles generating a large pool of membrane‐bound SGK1, which is differentially stabilized in lipid droplets (LD) in fed conditions or degraded in the endoplasmic reticulum by ER‐phagy in starvation. Association of the α‐helix to organelles does not depend on dedicated receptors or special phospholipids rather, it is intrinsic to its physicochemical properties and depends on the presence of bulky hydrophobic residues for attachment to LDs. The second mechanism is recruitment of protein‐chaperones that recognize the α‐helix as an unfolded protein promoting survival of the cytosolic SGK1 fraction. Together, the findings unveil an unexpected link between levels of energy storage and abundance of SGK1 and how changes in calorie intake could be used to modulate SGK1 expression, whereas the inhibition of molecular chaperones could serve as an additional enhancer in the treatment of malignancies and autoimmune disorders with high levels of SGK1 expression.