Seipin: from human disease to molecular mechanism

Abstract

The most-severe form of congenital generalized lipodystrophy (CGL) is caused by mutations in BSCL2/seipin. Seipin is a homo-oligomeric integral membrane protein in the endoplasmic reticulum that concentrates at junctions with cytoplasmic lipid droplets (LDs). While null mutations in seipin are responsible for lipodystrophy, dominant mutations cause peripheral neuropathy and other nervous system pathologies. We first review the clinical aspects of CGL and the discovery of the responsible genetic loci. The structure of seipin, its normal isoforms, and mutations found in patients are then presented. While the function of seipin is not clear, seipin gene manipulation in yeast, flies, mice, and human cells has recently yielded a trove of information that suggests roles in lipid metabolism and LD assembly and maintenance. A model is presented that attempts to bridge these new data to understand the role of this fascinating protein.

Fig. 1.

The human seipin gene, major transcripts, and mutations. A: Three coding transcripts, modified from NCBI Gene webpage for BSCL2. Exons are shown as rectangles, introns as lines with direction of transcription indicated. Open reading frames in dark green, untranslated regions in light green. Exon numbers are indicated. B: Seipin protein isoforms and mutations. Yellow boxes are the two consensus TMDs. Amino acids are numbered separately, corresponding to isoforms 1 and 2. Black lines, normal sequence; red line, aberrant sequence of isoform 3 due to out-of-register exon splicing. Dots and tents underneath indicate mutations. Red dots are truncation mutations, green dots are missense mutations, and red tents correspond to large deletions. Arrowheads indicate the two mutations in the glycosylation site. Mutation lettering corresponds to those listed in Table 1.

Fig. 2.

The seipin conundrum. Several abnormalities of lipid composition have been observed upon manipulating seipin expression, affecting PA, TAG, and a shift in balance of unsaturated and saturated FAs. Abnormalities in LD morphology have also been observed in seipin-deficient cells, including heterogenous LD size, LD clustering, LD wrapping in ER tangles, supersized/fusogenic LDs, and inefficient localization of LD surface proteins. Seipin may function directly in the metabolism of certain lipids, and this altered lipid composition in the absence of seipin may secondarily give rise to morphologically abnormal LDs (left). Alternatively, the direct function of seipin may be in organizing or maintaining LDs, and loss of seipin may affect lipid metabolic pathways by disrupting enzymes on the LD surface or in the ER bilayer (right). It may even be possible for these two hypothetical causal pathways to feed into each other.

Fig. 3.

Scenario for seipin function. A: Wild-type cells. Seipin regulates droplet formation by coupling TAG synthesis to droplet filling. This may involve interaction with DGAT or upstream enzymes in the pathway. In preadipocytes, the ER probably generates a ligand that activates adipogenesis through PPARγ. B: Seipin-deficient cells. In the absence of seipin, neutral lipid accumulates in the ER and has pleotropic effects on ER membrane function: lipid biosynthetic enzymes are dysregulated and the PPARγ ligand fails to be produced in sufficient amounts, or a receptor toxin such as PA is produced. Overproduced TAG leads to ectopic LDs that are functionally defective.