Size control of lipid droplets in budding yeast requires a collaboration of Fld1 and Ldb16

Abstract

The human congenital generalized lipodystrophy type 2 (CGL2) protein seipin/yeast Fld1 controls lipid droplet (LD) size through an unknown mechanism. Herein, we report that deletion of yeast LDB16/YCL005W, similar to FLD1, causes supersized and small clustered LDs, altered phospholipid metabolism, and impaired distribution of a subset of LD proteins. Ldb16 is a transmembrane protein in the endoplasmic reticulum (ER) that assembles together with Fld1 at ER/LD contact site, a region that likely links neutral lipid synthesis with LD assembly. The formation of the Fld1-Ldb16 complex involves their putative transmembrane segments, which directly contributes to the maintenance of LD morphology. The stability of Ldb16 requires Fld1, as Ldb16 is subjected to ER-associated degradation (ERAD) without Fld1 but stabilized when Fld1 is present. Strikingly, human seipin but not yeast Fld1 complements the LD defects in ldb16Δ, implying that seipin covers the function of the Fld1-Ldb16 complex. Together, we propose that human seipin may adopt the architecture of the yeast Fld1-Ldb16 complex for proper size maintenance of LDs.