Signaling pathways to the assembly of an interferon-beta enhanceosome - Chemical genetic studies with a small molecule

Small molecules that modulate specific protein functions are valuable tools for dissecting complex signaling pathways. Here, we identified a small mol ecule that induces the assembly of the interferon-beta (IFN-beta) enhanceos ome by stimulating all the enhancer-binding activator proteins: ATF2/c-JUN, IRF3, and p50/p65 of NF-kappa B. This compound stimulates mitogen-activate d protein kinase kinase kinase 1 (MEKK1), which is a member of a family of proteins involved in stress-mediated signaling pathways. Consistent with th is, MEKK1 activates IRF3 in addition to ATF2/c-JUN and NF-kappa B for the a ssembly of the IFN-beta enhanceosome. MEKK1 activates IRF3 through the c-JU N amino-terminal kinase (JNK) pathway but not the p38 and I kappa B kinase (IKK) pathway. Taken together with previous observations, these results imp licate that, for the assembly of an IFN-beta enhanceosome, MEKK1 can induce IRF3 and ATF2/c-JUN through the JNK pathway, whereas it can induce NF-kapp a B through the IKK pathway. Thus, specific MEKK family proteins may be abl e to integrate some of multiple signal transduction pathways leading to the specific activation of the IFN-beta enhanceosome.