A Janus kinase inhibitor, JAB, is an interferon-γ-inducible gene and confers resistance to interferons

It has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). However, molecular mechanism of regulation of IFN signaling has not been fully understood. We have reported novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. Here we report that JAB is strongly induced by IFN-γ but not by IFN-β in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH-3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-β and IFN-γ. M1 leukemic cells stably expressing JAB were also resistant to IFN-γ and IFN-β-induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-γ did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-γ-induced activation of JAK1 and JAK2 and IFN-β-induced JAK1 and Tyk2 activation were inhibited in NIH-3T3 JAB transformants. These results suggest that JAB inhibits IFN signaling by blocking JAK activity. We also found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STAT1 and JAK phosphorylation was partially reduced. Therefore, overexpression of JAB could be, at least in part, a mechanism of IFN resistance.