Mechanistic Insight into Phosphoregulation of the Lipin Family

Quietly emerging as essential regulators of lipid metabolism, the lipin protein family consisting of lipin 1, 2 and 3 are phosphatidic acid phosphatases that catalyze the penultimate step in triacylglycerol (TAG) biosynthesis, the conversion of phosphatidic acid to diacylglycerol.1 These soluble enzymes reversibly associate with the endoplasmic reticulum membrane, a distinction from the rest of TAG biosynthetic enzymes, which allow for dual function; lipin 1 also translocates into the nucleus to alter gene expression, thereby potentially linking lipid metabolism to gene expression. The importance of the lipin family in lipid metabolism is exemplified by mutant phenotypes. Loss of lipin 1 results in lipodystrophy and rhabdomyolysis in mouse and man, respectively, while loss of lipin 2 in humans results in Majeed’s syndrome.
In adipocytes, lipin 1 is downstream of the insulin/PI3K/mTOR signaling pathway, and is highly phosphorylated in response to insulin stimulation, which correlates with cytosolic location. The work herein has built upon the prior literature by examining how phosphorylation can alter lipin 1 localization. We have provided evidence that the lipins bind PA by the electrostatic hydrogen-bond switch mechanism through a PA binding domain consisting of nine basic amino acids and that this process is inhibited in a phosphorylation dependent manner, in the case of lipin 1, and independent, in the case of lipin 2. We have made the observation that lipin 1 forms high molecular weight complexes upon membrane binding, which have implications for lipin structure-function. In addition we demonstrate the rhabdomyolysis associated mutations in lipin 1 lead to defective PAP activity, providing a role for its phosphatase activity in the pathogenesis of this acute syndrome.