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JCS ePress online publication date 10 Jun 2003
doi: 10.1242/jcs.00528

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Research Article

The role of IFN{gamma} nuclear localization sequence in intracellular function


C.M. Iqbal Ahmed*, Marjorie A. Burkhart, Mustafa G. Mujtaba, Prem S. Subramaniam, and Howard M. Johnson
* Author for correspondence (e-mail: ahmed1{at}ufl.edu)

Intracellularly expressed interferon {gamma} (IFN{gamma}) has been reported to possess biological activity similar to that of IFN{gamma} added to cells. This study addresses the mechanisms for such similar biological effects. Adenoviral vectors were used to express a non-secreted form of human IFN{gamma} or a non-secreted mutant form in which a previously demonstrated nuclear localization sequence (NLS), 128KTGKRKR134, was replaced with alanines at K and R positions. With the vector expressing non-secreted wild-type IFN{gamma}, biological responses normally associated with extracellular IFN{gamma}, such as antiviral activity and MHC class I upregulation, were observed, although the mutant IFN{gamma} did not possess biological activity. Intracellular human IFN{gamma} possessed biological activity in mouse L cells, which do not recognize extracellularly added human IFN{gamma}. Thus, the biological activity was not due to leakage of IFN{gamma} to the surroundings and subsequent interaction with the receptor on the cell surface. Biological function was associated with activation of STAT1{alpha} and nuclear translocation of IFN{gamma}, IFNGR1 and STAT1{alpha}. Immunoprecipitation of cellular extracts with antibody to the nuclear transporter NPI-1 showed the formation of a complex with IFN{gamma}-IFNGR1-STAT1{alpha}. To provide the physiological basis for these effects we show that extracellularly added IFN{gamma} possesses intracellular signaling activity that is NLS dependent, as suggested by our previous studies, and that this activity occurs via the receptor-mediated endocytosis of IFN{gamma}. The data are consistent with previous observations that the NLS of extracellularly added IFN{gamma} plays a role in IFN{gamma} signaling.
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