Intracellular lipid surveillance by small G protein geranylgeranylation

• Published in: Nature (London) Vol. 605; no. 7911; pp. 736 - 740
• Main Authors: Watterson, Abigail, Tatge, Lexus, Wajahat, Naureen, Arneaud, Sonja L B, Solano Fonseca, Rene, Beheshti, Shaghayegh T, Metang, Patrick, Mihelakis, Melina, Zuurbier, Kielen R, Corley, Chase D, Dehghan, Ishmael, McDonald, Jeffrey G, Douglas, Peter M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 26.05.2022
• Subjects: Absorption; Animals; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Carbon; Conjugation; Depletion; Fatty acids; Homeostasis; Inactivation; Intracellular; Lipid metabolism; Lipids; Metabolism; Mitochondria; Monomeric GTP-Binding Proteins - metabolism; Mutation; Nuclear transport; Nutrients; Protein Prenylation; Proteins; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Regulation; Sterols; Surveillance; Transcription activation; Translocation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04729-7

Imbalances in lipid homeostasis can have deleterious effects on health . Yet how cells sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption remains unclear. Here we describe a mechanism for intracellular lipid surveillance in Caenorhabditis elegans that involves transcriptional inactivation of the nuclear hormone receptor NHR-49 through its cytosolic sequestration to endocytic vesicles via geranylgeranyl conjugation to the small G protein RAB-11.1. Defective de novo isoprenoid synthesis caused by lipid depletion limits RAB-11.1 geranylgeranylation, which promotes nuclear translocation of NHR-49 and activation of rab-11.2 transcription to enhance transporter residency at the plasma membrane. Thus, we identify a critical lipid sensed by the cell, its conjugated G protein, and the nuclear receptor whose dynamic interactions enable cells to sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption and lipid metabolism.