Status collaborative, led by the Manicassamy laboratory, with Han 2018 published from the University of Chicago with Balaji Manicassamy as corresponding author and Manivasagam 2025 with Priya Issuree and Balaji Manicassamy as corresponding authors. The discovery belongs to those groups. The tenOever contribution is recorded as one author in the Han 2018 list and as investigation in Manivasagam 2025 Areas Innate Immune Signaling and the Interferon Response
Safeguards against spontaneous antiviral activation had been described almost entirely upstream of transcription, acting on sensing and signalling through suppression of receptor components, post-translational modification, or editing of endogenous double-stranded RNA by ADAR1 so that MDA5 is not engaged. Interferon and interferon-stimulated gene promoters themselves were treated as sitting in a default off state awaiting an activated interferon regulatory factor or ISGF3, with FOXO3 repression of the Irf7 promoter as the noted exception. That leaves unexplained why basal expression is as low as it is in cells continuously generating host-derived double-stranded RNA.
Han 2018 recovered capicua, a conserved HMG-box repressor previously studied in development, cancer and neurodegeneration, from a survival-based genome-wide CRISPR screen whose dominant signal was sialic acid biosynthesis and transport. Loss of capicua restricted influenza A virus and also vesicular stomatitis, Zika and encephalomyocarditis viruses, raised antiviral gene expression under mock and infected conditions, and capicua protein fell between forty and sixty minutes after infection. Manivasagam 2025 converted that into a mechanism. Knockouts of capicua and of its obligate partner ATXN1L raised interferon and interferon-stimulated gene transcripts and restricted influenza A virus, reproduced by knockdown in primary human airway basal cells and by conditional knockout in mice. The basal signal required MAVS, which the authors read as tonic RIG-I-like receptor engagement by host-derived ligands. Chromatin accessibility rose at matching loci, reporter work with native and mutated binding-site motifs and a synthetic capicua carrying VP16 repeats established motif dependence in both directions, and the complex is degraded by the proteasome within forty minutes of synchronised infection, before genome replication, through EGFR-MAPK signalling, reproduced by recombinant hemagglutinin or by EGF alone and blocked by MEK or ERK inhibition. Capicua knockout mice lost less weight and carried 5 to 50-fold lower lung viral burden.
The consequence for the rest of this corpus is that a promoter's behaviour reflects both which activators are available and whether a repressor has been removed, which read against Schmid 2010 completes the picture from the repressive side. That combined reading is synthesis and is drawn in neither paper. Direct occupancy of endogenous loci was not measured in either study, the motif is the Drosophila consensus and is carried by 93 percent of the differentially accessible genes, the functional motif evidence comes from transfected reporters rather than native chromatin, and no ubiquitin ligase or ERK substrate site is identified. The line runs from an unexplained screen hit in 2018 to a characterised repressor in 2025 with a seven-year gap and no intervening publication in this corpus.
Substantiated by - Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication, identifies capicua as a repressor whose loss raises the antiviral set point across four virus families - Transcriptional repressor Capicua is a gatekeeper of cell-intrinsic interferon responses, places the repressor complex at motif-dependent loci during homeostasis and identifies the receptor-to-proteasome route that removes it
The Capicua and ATXN1L repressor complex binds an eight-nucleotide motif at interferon and interferon-stimulated gene loci to hold them repressed during homeostasis in human and mouse cells, and is degraded through EGFR-MAPK signaling early in respiratory viral entry, which relieves that repression.
A survival-based genome-wide CRISPR knockout screen in human lung epithelial cells selected with an avian H5N1 isolate recovers sialic acid biosynthesis and transport as the dominant requirement for influenza entry, with the CMP-sialic acid transporter SLC35A1 as the top hit, and identifies the transcriptional repressor capicua as a negative regulator of cell-intrinsic immunity.