Abstract
Membrane contact sites (MCSs) are regions of close apposition between different organelles that contribute to the functional integration of compartmentalized cellular processes. In recent years, we have gained insight into the molecular architecture of several contact sites, as well as into the regulatory mechanisms that underlie their roles in cell physiology. We provide an overview of two selected topics where lipid metabolism intersects with MCSs and organelle dynamics. First, the role of phosphatidic acid phosphatase, Pah1, the yeast homolog of metazoan lipin, toward the synthesis of triacylglycerol is outlined in connection with the seipin complex, Fld1/Ldb16, and lipid droplet formation. Second, we recapitulate the different contact sites connecting mitochondria and the endomembrane system and emphasize their contribution to phospholipid synthesis and their coordinated regulation. A comprehensive view is emerging where the multiplicity of contact sites connecting different cellular compartments together with lipid transfer proteins functioning at more than one MCS allow for functional redundancy and cross-regulation.
Highlights
Membrane contact sites (MCSs) are regions of close apposition between different organelles that contribute to the functional integration of compartmentalized cellular processes
The yeast S. cerevisiae has played a foundational role in the field of molecular and cellular biology of lipids, including the identification of membrane contact sites (MCSs) and how they link lipid metabolism with organelle dynamics
We review the contribution of Pah1 to lipid droplet (LD) formation and its interaction with the seipin complex, Fld1/Ldb16, to regulate endoplasmic reticulum (ER)-LD contact site dynamics
Summary
In addition to its function as a central precursor for PL and TAG syntheses, the pool of PA localized at the ER plays a regulatory role in modulating the expression of genes required for PL and fatty acid synthesis primarily through repressing transcription from genes containing an UASINO promoter element [3, 4, 43] (Fig. 2). In support of the notion that the phosphorylation status of Pah modulates its abundance, it was shown that a defective Nem1/Spo phosphatase complex attenuated the diminution of Pah level for cells reaching late exponential phase [13], as did rapamycin-mediated inhibition of TORC1 [49]. The expression of reporter genes driven from the PAH1 promoter increased as cells progressed into stationary phase, congruent with elevated PA phosphatase activity and TAG accumulation [53] This increment was not observed at the level of Pah abundance. In gis and rph mutants, PAH1 reporter gene expression showed loss of induction in stationary phase, as well as loss of inositol stimulation [53] Overall, these results reveal a complex network of transcriptional factors controlling the expression of PAH1 during growth, whose precise mechanism(s) has yet to be determined. Other protein kinases can phosphorylate Pah in vitro and many more phosphorylation sites have been identified on Pah that remain to be characterized [11, 54,55,56,57], underscoring the role of Pah as a signaling target for coordinating lipid metabolism with cellular processes
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