Abstract
BackgroundMembers of the signal transducer and activator of transcription (Stat) family of transcription factors traverse the nuclear membrane through a specialized structure, called the nuclear pore complex (NPC), which represents a selective filter for the import of proteins. Karyophilic molecules can bind directly to a subset of proteins of the NPC, collectively called nucleoporins. Alternatively, the transport is mediated via a carrier molecule belonging to the importin/karyopherin superfamily, which transmits the import into the nucleus through the NPC.Methodology/Principal FindingsIn this study, we provide evidence for an alternative Stat1 nuclear import mechanism, which is mediated by the shuttle protein nucleolin. We observed Stat1-nucleolin association, nuclear translocation and specific binding to the regulatory DNA element GAS. Using expression of nucleolin transgenes, we found that the nuclear localization signal (NLS) of nucleolin is responsible for Stat1 nuclear translocation. We show that this mechanism is utilized upon differentiation of myeloid cells and is specific for the differentiation step from monocytes to macrophages.Conclusions/SignificanceOur data add the nucleolin-Stat1 complex as a novel functional partner for the cell differentiation program, which is uniquely poised to regulate the transcription machinery via Stat1 and nuclear metabolism via nucleolin.
Highlights
Human blood monocytes are able to differentiate into morphologically and functionally heterogeneous effector cells, including macrophages
We addressed first these transcription factors and analyzed eluates of our pull-down assays using antibodies against signal transducer and activator of transcription (Stat) proteins. We found in these experiments that the transcription factor Stat1, but not other Stats (Stat2, Stat3, Stat4, Stat5), was bound to the nucleolin-GST matrix (Fig. 1A and data not shown)
This finding represents an alternative pathway to the already reported Stat1 nuclear translocation mechanisms, which is mediated by the shuttle protein nucleolin
Summary
Human blood monocytes are able to differentiate into morphologically and functionally heterogeneous effector cells, including macrophages. Recent studies highlight the role of transcription factors and other nucleocytoplasmic shuttling proteins in these processes, which require dynamic changes in gene expression [1,2]. Nucleolin has been implicated in many cellular activities, including pre-ribosomal RNA transcription and ribosome biogenesis [6], replication and recombination of DNA, cell cycle progression [7], viral infection [8,9], and apoptosis [10,11,12,13]. Members of the signal transducer and activator of transcription (Stat) family of transcription factors traverse the nuclear membrane through a specialized structure, called the nuclear pore complex (NPC), which represents a selective filter for the import of proteins. Karyophilic molecules can bind directly to a subset of proteins of the NPC, collectively called nucleoporins. The transport is mediated via a carrier molecule belonging to the importin/karyopherin superfamily, which transmits the import into the nucleus through the NPC
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