Nuclear Lipid Signaling

Abstract

There is now abundant evidence for the existence of phospholipids in the nucleus that resist washing of nuclei with detergents. These lipids are apparently not in the nuclear envelope, but are actually within the nucleus, presumably not in a bilayer membrane but instead forming proteolipid complexes with unidentified proteins. This review discusses the experimental evidence that attempts to explain their existence. Among these nuclear lipids are the polyphosphoinositol lipids which, together with the enzymes that synthesize them, form an intranuclear phospholipase C (PI-PLC) signaling system that generates diacylglycerol and inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. The isoforms of PI-PLC that are involved in this signaling system, and how they are regulated, are not yet clear. Generation of diacylglycerol within the nucleus is believed to recruit protein kinase C to the nucleus to phosphorylate intranuclear proteins. Generation of Ins(1,4,5)P3 may mobilize Ca2+ from the space between the nuclear membranes and thus increase nucleoplasmic Ca2+. Less well understood are an increasing number of variations and complications on the "simple" idea of a PI-PLC system. These include, all apparently within the nucleus: (i) two separate routes of synthesis of phosphatidylinositol-4,5-bisphosphate; (ii) two different sources of diacylglycerol, one being from the PI-PLC pathway, and the other probably from phosphatidylcholine; (iii) several different isoforms of PKC translocating to the nuclei; (iv) increases in activity of the PI-PLC pathway at two different points in the cell cycle; (v) a pathway of phosphorylation of Ins(1,4,5)P3, which may have several functions, including a role in the transfer of messenger RNA (mRNA) out of the nucleus; and (vi) the possible existence of other lipid signaling pathways that may include sphingolipids, phospholipase A2, and 3-phosphorylated inositol lipids.