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Epstein-Barr virus reactivation from latency promotes lytic replication, the production of infectious virions and exposes infected cells to recognition by the immune system. The key activator of EBV lytic cycle is Zta (BZLF1), a bZIP protein that binds to the host and viral genome and acts as a transcriptional regulator and origin binding protein. Zta is a homodimer with reported interactions with several of the conserved and essential herpes virus replication proteins and with several cellular transcription factors and signal transduction molecules. However, a full Zta interacting protein map is still missing. We used an unbiased approach to identify the viral and cellular Zta interactome during lytic reactivation of epithelial cells using chromatin immunoprecipitation combined with a label-free quantitative mass spectrometry. 55 proteins were found as Zta interacting proteins. Then the method was revised to identify the Zta interactome during lytic reactivation of Burkitt's lymphoma cells. The Zta interacting proteins were isolated by immunoprecipitation, followed by Tandem Mass Tag (TMT) labelling and mass spectrometry. 267 associated proteins were identified (FDR<0.05). This included previously identified viral (BMRF1, BALF5 and BGLF4) proteins. Cellular proteins were clustered by Gene ontology and several functional groups identified. HSC70 is central to one group. Its interaction with Zta was validated, demonstrated to occur independently of other viral proteins, and furthermore it was shown that HSC70 contributes to EBV lytic cycle. HSC70 is also targeted by other gamma herpes viruses during the viral lytic cycle, suggesting a conserved function. A second cluster contained NFAT proteins; these are calcium-signaling transcription factors. We validated that NFATc2 interacts with Zta. We present data that Zta attenuates calcium signalling regulated transcription activation through NFATs. As calcium signalling directly activates Zta expression during EBV reactivation, this establishes a negative feedback loop that dampens cellular activation.