PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production

The group IV cytosolic phospholipase A(2) (cPLA(2)) has been localized to t he nucleus (M. R. Sierra-Honigmann, J. R. Bradley, and J. S. Pober, Lab. In vestig. 74:684-695, 1996) and is known to translocate from the cytosolic co mpartment to the nuclear membrane CS. Clover, M. S. de Carvalho, T. Bayburt , M. Jonas, E. Chi, C. C. Leslie, and ill. H. Gelb, J. Biol. Chem. 270:1535 9-15367, 1995; A. R. Schievella, M. K. Regier, W L. Smith, and L. L. Lin, J . Biol. Chem. 270:30749-30754, 1995). We hypothesized that nuclear proteins interact with cPLA(2) and participate in the functional effects of this tr anslocation. We have identified a nuclear protein, cPLA(2)-interacting prot ein (PLIP), a splice variant of human Tip60, which interacts with the amino terminal region of cPLA(2). Like Tip60, FLIP cDNA includes the MYST domain containing a C2HC zinc finger and well-conserved similarities to acetyltra nsferases, Both PLIP and Tip60 coimmunoprecipitate and colocalize with cPLA (2) within the nuclei of transfected COS cells. A polyclonal antibody raise d to PLIP recognizes both FLIP and Tip60. Endogenous Tip60 and/or FLIP in r at mesangial cells is localized to the nucleus in response to serum depriva tion. Nuclear localization coincides temporally with apoptosis. FLIP expres sion, mediated by adenoviral gene transfer, potentiates serum deprivation-i nduced prostaglandin E-2 (PGE(2)) production and apoptosis in mouse mesangi al cells from cPLA(2)(+/+) mice but not in mesangial cells derived from cPL A(2)(-/-) mice. Thus FLIP, a splice variant of Tip60, interacts with cPLA(2 ) and potentiates cPLA(2)-mediated PGE(2) production and apoptosis.