SUMMARY PARAGRAPH for SCS2
SCS2 encodes a type II integral membrane protein and VAP (VAMP/synaptobrevin-associated protein) family member that localizes to both the endoplasmic reticulum (ER) and nuclear membranes (2, 9) where it regulates intracellular lipid traffic and phospholipid biosynthesis (9). A region of Scs2p that is conserved in VAP family members constitutes the binding site for a short membrane-targeting determinant called the FFAT motif (two phenylalanines (FF) in an Acidic Tract). The FFAT motif is located in several sterol-binding proteins involved in intracellular sterol transport (Swh1p, Osh2p and Osh3p) and in a transcriptional corepressor of phospholipid biosynthetic genes (Opi1p) (5, 9). Interactions between Scs2p and the sterol-binding proteins regulate intracellular lipid transport by targeting these proteins to the ER membrane, the site of synthesis for most lipids (9). Under conditions where inositol is limiting and the unfolded protein response (UPR) activated, direct interactions between Scs2p and Opi1p sequester this transcriptional regulator at the ER/nuclear membrane where it can then bind to phosphatidic acid (PA) (9, 10, 11). Upon the addition of inositol, the lipid precursor phosphatidic acid (PA) and cytidyldiphosphate diacylglycerol (CDP-DAG) are converted into phosphatidylinositol (PI), resulting in the consumption of PA, and the release of Opi1p from the membrane followed by its nuclear translocation (reviewed in 12). Thus by regulating the intracellular location of this lipid-sensing transcriptional regulator, Scs2p regulates the negative feedback loop that controls expression of inositol biosynthetic genes. Scs2p also directly regulates the intranuclear localization of the gene encoding inositol 1-phosphate synthase (INO1), the rate-limiting enzyme in inositol biosynthesis (10).
SCS2 was originally identified as a suppressor of the inositol auxotrophy associated with a dominant choline sensitive mutant (8) and with hac1 mutants, both of which are also defective for expression of INO1 (1). scs2 deletion mutants have reduced levels of phosphatidylinositol, increased levels of phophatidylcholine and a leaky inositol auxotrophy when cultured at elevated temperatures (2, 4). The leaky inositol auxotrophy is suppressed by overexpression of INO1 or INO2, or by deletion of genes in the CDP-choline pathway (CKI1, PCT1, and CPT1), a pathway that is upregulated in scs2 deletion mutants (2, 4). Deletion of SCS22, an SCS2-like gene, does not result in inositol auxotrophy but does contribute to the regulation of phospholipid metabolism, as the phenotype associated with the double mutant is more severe than that of an scs2 single mutant (5). SCS2 has also been identified as a multicopy suppressor of strains with telomere silencing defects (3, 13), while deletion of SCS2 results in a loss of telomeric silencing (3).
SCS2 has sequence similarity with members of the VAP protein family including the founding member, VAP-33, an Aplysia gene required for neurotransmitter release (reviewed in 14). Three human VAP family members VAP-A (OMIM), VAP-B (OMIM) and VAP-C (OMIM) (a VAP-B splicing variant) (15) are also involved in recruiting FFAT-motif containing lipid-binding proteins to the ER (16, 5). Human VAP family members have also been implicated in both vesicular trafficking and organization of microtubule networks (references found within 17). The human VAP-A gene can partially complement the function of yeast VAPs by rescuing the inositol auxotrophy of an scs2 scs22 double mutant under less stringent conditions, and this rescue is dependent upon the integrity of the FFAT-binding region of VAP-A (5). Mutations in the human VAP-B gene cause atypical amyotrophic lateral sclerosis (ALS) type 8 (a neurodegenerative disease also known as Lou Gehrig's disease; OMIM), and late-onset spinal muscular atrophy (SMA) (OMIM) (18).
Last updated: 2007-06-01