Editing Interferon (section)

==Downstream signaling==
By interacting with their specific receptors, IFNs activate ''signal transducer and activator of transcription'' ([[STAT protein|STAT]]) complexes; STATs are a family of [[transcription factor]]s that regulate the expression of certain immune system genes.  Some STATs are activated by both type I and type II IFNs.  However each IFN type can also activate unique STATs.<ref name="pmid15864272">{{cite journal | vauthors = Platanias LC | title = Mechanisms of type-I- and type-II-interferon-mediated signalling | journal = Nature Reviews. Immunology | volume = 5 | issue = 5 | pages = 375–386 | date = May 2005 | pmid = 15864272 | doi = 10.1038/nri1604 | s2cid = 1472195 | doi-access = free }}</ref>

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical [[Janus kinase]]-STAT ([[JAK-STAT]]) signaling pathway.<ref name="pmid15864272"/>  In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, [[phosphorylation|phosphorylate]] both [[STAT1]] and [[STAT2]].  As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called [[ISGF3G|IRF9]]—and moves into the [[cell nucleus]]. Inside the nucleus, the ISGF3 complex binds to specific [[nucleotide]] sequences called ''IFN-stimulated response elements'' (ISREs) in the [[promoter (biology)|promoter]]s of certain [[gene]]s, known as IFN stimulated genes [[ISGs]]. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes.<ref name="pmid15864272"/> A collection of known ISGs is available on [[Interferome]], a curated online database of ISGs ([https://web.archive.org/web/20131011000719/http://www.interferome.org/ www.interferome.org]);<ref>{{cite journal | vauthors = Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ | title = INTERFEROME: the database of interferon regulated genes | journal = Nucleic Acids Research | volume = 37 | issue = Database issue | pages = D852–D857 | date = January 2009 | pmid = 18996892 | pmc = 2686605 | doi = 10.1093/nar/gkn732 }}</ref> Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these [[protein dimer|dimer]]s initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters.<ref name="pmid15864272"/>  Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element.<ref name="pmid15864272"/>

In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades.  For instance, both type I and type II IFNs activate a member of the CRK family of [[Signal transducing adaptor protein|adaptor protein]]s called [[CRKL]], a nuclear adaptor for [[STAT5]] that also regulates signaling through the [[RAPGEF1|C3G]]/[[Rap1]] pathway.<ref name="pmid15864272"/>  Type I IFNs further activate ''[[p38 mitogen-activated protein kinase]]'' (MAP kinase) to induce gene transcription.<ref name="pmid15864272"/>  Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling.  The ''[[phosphatidylinositol 3-kinase]]'' (PI3K) signaling pathway is also regulated by both type I and type II IFNs.  PI3K activates [[P70-S6 Kinase 1]], an enzyme that increases protein synthesis and cell proliferation; phosphorylates [[ribosomal protein s6]], which is involved in protein synthesis; and phosphorylates a translational repressor protein called ''eukaryotic translation-initiation factor 4E-binding protein 1'' ([[EIF4EBP1]]) in order to deactivate it.<ref name="pmid15864272"/>

Interferons can disrupt signaling by other stimuli. For example, interferon alpha induces RIG-G, which disrupts the CSN5-containing COP9 signalosome (CSN), a highly conserved multiprotein complex implicated in protein deneddylation, deubiquitination, and phosphorylation.<ref name="Xu_2013">{{cite journal | vauthors = Xu GP, Zhang ZL, Xiao S, Zhuang LK, Xia D, Zou QP, Jia PM, Tong JH | title = Rig-G negatively regulates SCF-E3 ligase activities by disrupting the assembly of COP9 signalosome complex | journal = Biochemical and Biophysical Research Communications | volume = 432 | issue = 3 | pages = 425–430 | date = March 2013 | pmid = 23415865 | doi = 10.1016/j.bbrc.2013.01.132 }}</ref>  RIG-G has shown the capacity to inhibit NF-κB and STAT3 signaling in lung cancer cells, which demonstrates the potential of type I IFNs.<ref>{{Cite journal |last1=Li |first1=Dong |last2=Sun |first2=Junjun |last3=Liu |first3=Wenfang |last4=Wang |first4=Xuan |last5=Bals |first5=Robert |last6=Wu |first6=Junlu |last7=Quan |first7=Wenqiang |last8=Yao |first8=Yiwen |last9=Zhang |first9=Yu |last10=Zhou |first10=Hong |last11=Wu |first11=Kaiyin |date=2016-10-04 |title=Rig-G is a growth inhibitory factor of lung cancer cells that suppresses STAT3 and NF-κB |journal=Oncotarget |volume=7 |issue=40 |pages=66032–66050 |doi=10.18632/oncotarget.11797 |issn=1949-2553 |pmc=5323212 |pmid=27602766}}</ref>