15-Deoxy-Δ12,14-prostaglandin J2 Impairs Phosphatidylcholine Synthesis and Induces Nuclear Accumulation of Thiol-modified Cytidylyltransferase*

摘要

Synthesis of phosphatidylcholine, the major phospholipid of animal cellmembranes, requires the key enzyme cytidylyltransferase (CCTα). Cysteinesulfhydryls within CCTα are needed for full catalytic activity. Here weshow that prostaglandin 15-deoxy-Δ12,14-PGJ2(15d-PGJ2) inactivates CCTα by inducing generation ofreactive oxidant species and the appearance of a cross-linked CCTα dimerin cells. N-Acetyl-l-cysteine reduced oxidative stress,prevented CCTα cross-linking, and restored CCT function in15d-PGJ2-treated cells. 15d-PGJ2 modified criticalcysteine residues within CCTα as determined by mutagenesis studies andby incorporation of biotin-15d-PGJ2 into CCTα. These effectsof 15d-PGJ2 were associated with CCTα accumulation within thenucleus. The data indicate that bioactive prostanoids significantly impairmembrane phospholipid production by promoting cysteine cross-bridging withinCCTα.