Intracellular lipid surveillance by small G protein geranylgeranylation

• Published in: Nature (London) 2022-05, Vol.605 (7911), p.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: Article
• Language: English
• Subjects: 101/58; 14/19; 38; 38/35; 38/89; 38/91; 631/337/458/2133; 631/45/287/1183; 631/80/313/2011; 64/11; 82/29; 96/31; Absorption; Animals; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Carbon; Conjugation; Depletion; Fatty acids; Homeostasis; Humanities and Social Sciences; Inactivation; Intracellular; Lipid metabolism; Lipids; Metabolism; Mitochondria; Monomeric GTP-Binding Proteins - metabolism; multidisciplinary; Mutation; Nuclear transport; Nutrients; Protein Prenylation; Proteins; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Regulation; Science; Science (multidisciplinary); Sterols; Surveillance; Transcription activation; Translocation
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-04729-7

Imbalances in lipid homeostasis can have deleterious effects on health 1 , 2 . 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. In Caenorhabditis elegans , geranylgeranyl conjugation to RAB-11.1 acts as a lipid sensor to regulate nutrient uptake and lipid metabolism in response to metabolic demand.