title: Type I IFN receptor controls activated TYK2 in the nucleus: implications for EAE therapy.
abstract: Recent studies have suggested that activated wild-type and mutant Janus kinase JAK2 play a role in the epigenetics of histone modification, where it phosphorylates histone H3 on tyrosine 41(H3pY41). We showed that type I IFN signaling involves activated TYK2 in the nucleus. ChIP-PCR demonstrated the presence of receptor subunits IFNAR1 and IFNAR2 along with TYK2, STAT1, and H3pY41 specifically at the promoter of the OAS1 gene in IFN treated cells. A complex of IFNAR1, TYK2, and STAT1α was also shown in the nucleus by immunoprecipitation. IFN treatment was required for TYK2 activation in the nucleus. The presence of IFNAR1, IFNAR2, and activated STAT1 and STAT2, as well as the type I IFN in the nucleus of treated cells was confirmed by the combination of Western blotting and confocal microscopy. Trimethylated histone H3 lysine 9 underwent demethylation and subsequent acetylation specifically in the region of the OAS1 promoter. Resultant N-terminal truncated IFN mimetics functioned intracellularly as antivirals as well as therapeutics against experimental allergic encephalomyelitis without the undesirable side effects that limit the therapeutic efficacy of IFNβ in treatment of multiple sclerosis. The findings indicate that IFN signaling is complex like that of steroid signaling.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, United States. ahmed1@ufl.edu
authors.forename: Chulbul M
authors.initials: CM
authors.lastname: Ahmed
authors.forename: Ezra N
authors.initials: EN
authors.lastname: Noon-Song
authors.forename: Kaisa
authors.initials: K
authors.lastname: Kemppainen
authors.forename: Massimo P
authors.initials: MP
authors.lastname: Pascalli
authors.forename: Howard M
authors.initials: HM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D047369:Chromatin Immunoprecipitation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells / Q000648:ultrastructure; D006801:Humans; D016898:Interferon-alpha / Q000737:chemistry; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D053634:TYK2 Kinase / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D016895:Culture Media, Serum-Free; D016898:Interferon-alpha; D010455:Peptides; D050791:STAT Transcription Factors; D049452:Green Fluorescent Proteins; D053633:Receptor, Interferon alpha-beta; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse