LDAF1 and Seipin Form a Lipid Droplet Assembly Complex

• Published in: Developmental cell Vol. 51; no. 5; pp. 551 - 563.e7
• Main Authors: Chung, Jeeyun, Wu, Xudong, Lambert, Talley J., Lai, Zon Weng, Walther, Tobias C., Farese, Robert V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.12.2019
• Subjects: Berardinelli-Seip congenital lipodystrophy type 2; Cell Line, Tumor; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; fat; GTP-Binding Protein gamma Subunits - metabolism; HEK293 Cells; Humans; lipid droplets; Lipid Droplets - metabolism; lipodystrophy; Membrane Proteins - metabolism; organelle biogenesis; promethin; Protein Binding; TMEM159; triacylglycerol; Triglycerides - metabolism; triacylglycerol; TMEM159; fat; organelle biogenesis; Berardinelli-Seip congenital lipodystrophy type 2; lipid droplets; endoplasmic reticulum; lipodystrophy; promethin
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.10.006

Lipid droplets (LDs) originate from the endoplasmic reticulum (ER) to store triacylglycerol (TG) and cholesterol esters. The ER protein seipin was shown to localize to ER-LD contacts soon after LDs form, but what determines the sites of initial LD biogenesis in the ER is unknown. Here, we identify TMEM159, now re-named lipid droplet assembly factor 1 (LDAF1), as an interaction partner of seipin. Together, LDAF1 and seipin form an ∼600 kDa oligomeric complex that copurifies with TG. LDs form at LDAF1-seipin complexes, and re-localization of LDAF1 to the plasma membrane co-recruits seipin and redirects LD formation to these sites. Once LDs form, LDAF1 dissociates from seipin and moves to the LD surface. In the absence of LDAF1, LDs form only at significantly higher cellular TG concentrations. Our data suggest that the LDAF1-seipin complex is the core protein machinery that facilitates LD biogenesis and determines the sites of their formation in the ER. [Display omitted] •LDAF1 and seipin form an ∼600 kDa oligomeric complex in the ER bilayer•The LDAF1-seipin complex determines the sites of lipid droplet formation in the ER•LDAF1 dissociates from seipin and moves to the growing lipid droplet surface•LDAF1 facilitates lipid droplet formation at low ER triglyceride concentration Chung et al. identify and characterize an oligomeric LDAF1-seipin protein complex in the endoplasmic reticulum that determines the sites of lipid droplet formation. This complex appears to promote phase separation of triglyceride neutral lipids within the complex, thus defining the sites of lipid droplet formation.