Identification of TMEM263 as an ER-resident protein that controls early stages of lipid droplet biogenesis

Abstract Cell and organismal growth is controlled not only by the availability of nutrients, but also the ability to dynamically sense and respond to changes in metabolic demand. We have identified a protein, TMEM263 (also known as C12orf23) as a mechanistic link between growth and lipid metabolism. TMEM263 was discovered in a screen as an ER-resident protein, and we have characterised its role as both necessary and sufficient for lipid droplet formation. TMEM263 has two transmembrane domains that fold into a dynamic alpha hairpin which are essential for its localisation to the ER and to support lipid droplet accumulation. Functionally, we propose that TMEM263 can interact with and support the condensation of neutral lipids in a bilayer to promote lipid droplet formation and growth. Consistently, loss of TMEM263 in cells and in zebrafish significantly impairs lipid droplet accumulation. Loss of TMEM263 protein function in vivo is associated with organismal growth defects and proportional dwarfism and our study provides a mechanistic understanding linking these phenotypes to impaired lipid droplet biology.