Wang Chao-Wen, Miao Yu-Hsuan, Chang Yi-Shun
Institute of Plant and Microbial Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan.
J Cell Sci. 2014 Mar 15;127(Pt 6):1214-28. doi: 10.1242/jcs.137737. Epub 2014 Jan 16.
The human congenital generalized lipodystrophy type 2 protein seipin (Fld1 in budding yeast) controls lipid droplet (LD) size through an unknown mechanism. Here, we report that deletion of yeast LDB16/YCL005W, similar to deletion of 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 sites, a region that probably links neutral lipid synthesis with LD assembly. The formation of the Fld1-Ldb16 complex involves putative transmembrane segments of both proteins, thus, directly contributing to the maintenance of LD morphology. The stability of Ldb16 requires Fld1, as Ldb16 is subjected to ER-associated degradation (ERAD) in the absence of Fld1 but is stabilized when Fld1 is present. Strikingly, human seipin, but not yeast Fld1, complements the defects in LDs in ldb16Δ yeast, implying that seipin can substitute for the function of the Fld1-Ldb16 complex. We propose that human seipin might adopt the architecture of the yeast Fld1-Ldb16 complex in order to properly maintain the size of LDs.
人类2型先天性全身脂肪营养不良蛋白seipin（芽殖酵母中的Fld1）通过未知机制控制脂滴（LD）的大小。在此，我们报道，与Fld1缺失类似，酵母LDB16/YCL005W的缺失会导致超大且成簇的小脂滴、磷脂代谢改变以及一部分脂滴蛋白的分布受损。Ldb16是内质网（ER）中的一种跨膜蛋白，它与Fld1在内质网 - 脂滴接触位点组装在一起，该区域可能将中性脂质合成与脂滴组装联系起来。Fld1 - Ldb16复合物的形成涉及两种蛋白质的假定跨膜片段，因此直接有助于维持脂滴形态。Ldb16的稳定性需要Fld1，因为在没有Fld1的情况下，Ldb16会遭受内质网相关降解（ERAD），而当有Fld1存在时它会稳定下来。引人注目的是，人类seipin而非酵母Fld1能够弥补ldb16Δ酵母中脂滴的缺陷，这意味着seipin可以替代Fld1 - Ldb16复合物的功能。我们提出，人类seipin可能采用酵母Fld1 - Ldb16复合物的结构来适当地维持脂滴的大小。
