Nuclear transit of the intracellular domain of the interferon receptor subunit IFNaR2 requires Stat2 and Irf9.

Regulated intramembrane proteolysis (RIP) is the primary signaling mechanism for some receptors, such as Notch and the amyloid precursor protein. In addition, some receptor type tyrosine kinases, such as HER4, are able to signal via both kinase activation and regulated receptor proteolysis. Previously, we showed that the IFNaR2 subunit of the type I interferon receptor can be cleaved in a two step process that resembles RIP and that the IFNaR2 intracellular domain (IFNaR2-ICD) can mediate gene transcription in a Stat2 dependent manner. Here, we demonstrate that IFNaR2-ICD, Stat2 and Irf9 form a ternary complex. Furthermore, Stat2 and Irf9 are required for the nuclear transit of a GFP-linked IFNaR2-ICD construct (GFP-ICD). Additional experiments monitoring the nuclear localization of GFP-ICD demonstrate that Stat2 serves an adaptor role, mediating the interaction between the IFNaR2-ICD and Irf9, while the bipartite nuclear localization signal within Irf9 is the primary determinant driving nuclear transit of the ICD containing complex. Overall, the data suggest that liberation of the IFNaR2-ICD by regulated proteolysis could trigger a novel mechanism for moving the transcription factor Stat2 to the nucleus.

Iodinated contrast prior to thrombolysis was not associated with worse intracranial hemorrhage.

OBJECTIVES: The objective was to assess relative incidence of clinical adverse effects between patients receiving, and not receiving, iodinated contrast prior to thrombolysis. METHODS: This was a retrospective registry review of patients presenting to the emergency department treated with recombinant tissue-type plasminogen activator (rt-PA) for acute ischemic stroke between 2004 and 2012. The authors compared the occurrence of all grades of intracranial hemorrhage (ICH), symptomatic intracranial hemorrhage (sICH), and in-hospital deaths between patients undergoing computed tomographic angiography (CTA) prior to thrombolysis and those who did not. RESULTS: A total of 1,014 patients were available for analysis meeting inclusion criteria. A total of 473 patients underwent CTA prior to rt-PA administration. Baseline characteristics were generally similar across groups, excepting fewer signs of acute infarct and old stroke in the CTA group (28.8% vs. 8.5% and 9.9% vs. 3.7%, respectively) and creatinine. Adverse event outcomes were not consistently distributed across the groups. Patients in the CTA group had a similar incidence of any ICH (11.0% vs. 8.1%, p = 0.120), but fewer type II parenchymal hemorrhages (2.1% vs. 4.6%, p = 0.025) and fewer in-hospital deaths (7.2% vs. 12.6%, p = 0.005). CONCLUSIONS: No consistent harms were observed in association with intravenous iodinated contrast prior to rt-PA administration. It is reasonable to continue CTA prior to thrombolysis as clinically indicated.