A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.
Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.
Donkor
Jimmy
J
Department of Human Genetics and Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA.
Zhang
Peixiang
P
Wong
Samantha
S
O'Loughlin
Lauren
L
Dewald
Jay
J
Kok
Bernard P C
BP
Brindley
David N
DN
Reue
Karen
K
D019943:Amino Acid Substitution; D000742:Anemia, Dyserythropoietic, Congenital / Q000201:enzymology / Q000235:genetics; D000818:Animals; D002460:Cell Line; D003872:Dermatitis / Q000201:enzymology / Q000235:genetics; D005334:Fever / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D010019:Osteomyelitis / Q000201:enzymology / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome
C502575:LPIN2 protein, human; D009687:Nuclear Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D012694:Serine; C485999:LPIN1 protein, human; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; C540254:Lipin 2 protein, mouse