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It is well established that interferons trigger tyrosine-kinase-dependent signaling via JAK kinases and STAT transcription factors. However, we have observed both IFNaR2 receptor cleavage and functional activity of the liberated intracellular domain (ICD), suggesting that interferon-alpha (IFN-alpha) can also signal via regulated intramembrane proteolysis (RIP), an evolutionarily conserved mechanism of receptor-mediated signaling. Sequential cleavage of the receptor ectodomain and transmembrane domain is a hallmark of the most common class of RIP. To investigate the mechanisms of IFNaR2 RIP signaling, we examined IFNaR2 cleavage by TNF-alpha converting enzyme (TACE) and presenilin proteases. We tracked the fate of epitope-tagged and fusion variants of IFNaR2 in cells expressing wild-type, mutant, or null versions of TACE and presenilins 1 and 2. Cleavage and subcellular location were determined by immunoblot, fluoresence microscopy, and reporter assays. We found that both TACE and presenilin 1/2 cleave IFNaR2, in a sequential manner that allows the ICD to move to the nucleus. TACE cleavage was induced by IFN-alpha but was not consistently required for the anti-proliferative effects of IFN-alpha. In conclusion, IFNaR2 is cleaved by TACE and Presenilin 1/2, suggesting that interferons signal by both kinase and RIP-mediated pathways.

Sequential Proteolytic Processing of an Interferon-Alpha Receptor Subunit by TNF-Alpha Converting Enzyme and Presenilins