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First published online 10 June 2003
doi: 10.1242/jcs.00528
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Research Article |
nuclear localization sequence in intracellular function
Department of Microbiology and Cell Science, University of Florida, P.O. Box 110700, Gainesville, FL, 32611-0700, USA
* Author for correspondence (e-mail: ahmed1{at}ufl.edu)
Accepted 1 April 2003
Intracellularly expressed interferon 
(IFN) has been reported
to possess biological activity similar to that of IFN 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 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, biological responses normally associated
with extracellular IFN, such as antiviral activity and MHC class I
upregulation, were observed, although the mutant IFN did not possess
biological activity. Intracellular human IFN possessed biological
activity in mouse L cells, which do not recognize extracellularly added human
IFN. Thus, the biological activity was not due to leakage of IFN
to the surroundings and subsequent interaction with the receptor on the cell
surface. Biological function was associated with activation of STAT1
and nuclear translocation of IFN, IFNGR1 and STAT1.
Immunoprecipitation of cellular extracts with antibody to the nuclear
transporter NPI-1 showed the formation of a complex with
IFN-IFNGR1-STAT1. To provide the physiological basis for these
effects we show that extracellularly added IFN 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. The data are consistent with previous observations that the NLS
of extracellularly added IFN plays a role in IFN signaling.
Key words: Inteferon , Nuclear localization sequence (NLS), STAT1, MHC
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