14-3-3ζ escorts CCTα for calcium-activated nuclear import in lung epithelia

Integrity of animal biomembranes is critical to preserve normal cellular functions and viability. Phosphatidylcholine, an indispensible membrane component, requires the enzyme CCT alpha for its biosynthesis. Nuclear expression of CCT alpha is needed for expansion of the nuclear membrane network, but mechanisms for CCT alpha nuclear import are unknown. Herein, we show that in epithelia, extracellular Ca2+ triggers CCT alpha cytoplasmic-nuclear translocation. CCT alpha nuclear import was associated with binding to 14-3-3 zeta, a key regulator of protein trafficking. 14-3-3 zeta was both sufficient and required for CCT alpha nuclear import. Helix G within the 14-3-3 zeta binding groove interacts with a putative molecular signature within the CCT alpha carboxyl-terminal phosphoserine motif (residues 328-343). 14-3-3 zeta was critically involved in preserving phosphatidylcholine synthesis and cell viability in a model of Pseudomonas aeruginosa infection where Ca2+ concentrations increase within epithelia. Thus, 14-3-3 zeta controls CCT alpha nuclear import in response to calcium signals, thereby regulating mammalian phospholipid synthesis. Agassandian, M., Chen, B. B., Schuster, C. C., Houtman, J. C. D., Mallampalli, R. K. 14-3-3 zeta escorts CCT alpha for calcium-activated nuclear import in lung epithelia. FASEB J. 24, 1271-1283 (2010). www.fasebj.org