(490.2) STAT3 Nuclear Accumulation Due to Loss of RanBP2 May Contribute to Pathogenesis of Acute Necrotizing Encephalopathy

Poster Board Number: A99

Emilee Spozarski (Westminster College), Karen Resendes (Westminster College)

Ran Binding Protein 2 (RanBP2) contributes to the efficiency of nuclear import and export from its position at the cytoplasmic filaments of the nuclear pore complex.  Here it can recruit import receptors, mediate efficient loading of cargo proteins onto importins, and serve as a docking site to efficiently recycle import and export complexes.  Loss of function mutations in the RanBP2 gene are observed in many familial cases of acute necrotizing encephalopathy (ANE), a rare, sometimes fatal brain disease often occurring in infancy or early childhood following a viral infection.  The influence of the RanBP2 mutation on the pathogenesis of ANE is unknown, but research points to a connection to the associated cytokine storm resulting from abnormal cytokine production. Specifically, the hyperactivation of the IL-6/JAK/STAT3 cytokine signaling pathway has been observed in patients with ANE.  We aimed to investigate a possible relationship between RanBP2 and STAT3 nuclear transport to determine if a loss of RanBP2 could influence the cellular localization of the transcription factor STAT3.  Due to RanBP2’s importance in maintaining the efficiency of nuclear transport, its absence could impact either the nuclear or cytoplasmic localization of STAT3.  siRNA knockdown of RanBP2 caused a 27% increase of STAT3 in the nucleus, suggesting increased STAT3 induced cytokine gene expression may occur without RanBP2.  Our ongoing studies involve testing RanBP2 knockdown in conjunction with IL-6 treatment to determine if there is an additional effect on the cellular localization of STAT3 with the activation of signaling. Accumulation of STAT3 in the nucleus alone could contribute to the onset of ANE, however STAT3 typically requires activation of signaling to increase gene expression.  Our current results established increased nuclear STAT3 as a potential mechanism for mutation of RanBP2 to influence escalated cytokine production, perpetuating cytokine storm in ANE.