title: Sequential proteolytic processing of an interferon-alpha receptor subunit by TNF-alpha converting enzyme and presenilins.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, IRVINE, Irvine, CA 92697, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Pioli
authors.forename: Abu M Z
authors.initials: AM
authors.lastname: Saleh
authors.forename: Ashraf
authors.initials: A
authors.lastname: El Fiky
authors.forename: Kent L
authors.initials: KL
authors.lastname: Nastiuk
authors.forename: John J
authors.initials: JJ
authors.lastname: Krolewski
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053763:Presenilins; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse