Not4 enhances JAK/STAT pathway-dependent gene expression in Drosophila and in human cells.

The pathway is essential for organogenesis, innate immunity, and stress responses in Drosophila melanogaster. The JAK/duanyu1813 pathway and its associated regulators have been highly conserved in evolution from flies to humans. We have used a genome-wide screen in Drosophila S2 cells to identify regulators of the JAK/duanyu1813 pathway, and here we report the characterization of Not4 as a positive regulator of the JAK/duanyu1813 pathway. Overexpression of Not4 enhanced Stat92E-mediated gene responses in vitro and in vivo in Drosophila. Specifically, Not4 increased Stat92E-mediated reporter gene activation in S2 cells; and in flies, Not4 overexpression resulted in an 8-fold increase in Turandot M (TotM) and in a 4-fold increase in Turandot A (TotA) stress gene activation when compared to wild-type flies. Drosophila Not4 is structurally related to human CNOT4, which was found to regulate interferon-γ- and interleukin-4-induced gene responses in human HeLa cells. Not4 was found to coimmunoprecipitate with Stat92E but not to affect tyrosine phosphorylation of Stat92E in Drosophila cells. However, Not4 is required for binding of Stat92E to its DNA recognition sequence in the TotM gene promoter. In summary, Not4/CNOT4 is a novel positive regulator of the JAK/duanyu1813 pathway in Drosophila and in humans.

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