{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE329nnn/GSE329545/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329545"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Mechanisms of Differential Signaling by IFNLR1 Variants","description":"Introduction: Lambda interferons signal through the interferon lambda receptor-1 (IFNLR1) and IL10RB heterodimer to induce interferon stimulated genes (ISGs). We previously showed that proteins derived from distinct IFNLR1 splice isoforms uniquely influence gene expression and HBV replication in stem cell-derived hepatocytes (iHeps). Here, we evaluated the mechanisms of signal transduction by full-length IFNLR1 (variant 1) and a truncated variant missing part of the cytoplasmic JAK1-interacting domain (variant 2). Methods: We evaluated HEK293T cells, wild-type (WT), and IFNLR1 knock-out (KO) iHeps with doxycycline-inducible expression FLAG-tagged IFNLR1 variants using the Duolink proximity ligation assay, ImageStream flow cytometry, western blotting of JAK-STAT proteins, susceptibility to JAK1 and TYK2 inhibitors, and gene expression profiling. Results: Each variant demonstrated IFNL-induced colocalization with IL10RB, but variant 1 was more rapidly and extensively internalized. In WT iHeps with intact endogenous IFNLR1, overexpression of either variant 1 or variant 2 enabled higher IFNL-induced JAK1, TYK2, STAT1 and STAT2 phosphorylation, yet variant 2 supported less robust ISG induction than variant 1. In iHeps with abrogated endogenous IFNLR1 expression, variant 2 supported less JAK1 and TYK2 phosphorylation and ISG induction than variant 1 yet was not deficient in supporting STAT1 and STAT2 phosphorylation. Select ISGs had differential constitutive expression in IFNL-untreated variant-expressing iHeps. In iHeps expressing variant 1, WT-iHeps were more resistant than KO-iHeps to TYK2-inhibition of antiviral ISG induction yet conversely were more susceptible to TYK2-inhibition of proinflammatory ISG induction, suggesting endogenously produced noncanonical variants influence the TYK2-dependence of IFNL signaling. Conclusions: IFNLR1 variants promote differential utilization of signaling mediators to influence IFNL-induced gene expression patterns, indicating a putative role in pathway regulation.","dates":{"publication":"2026/04/30"},"accession":"GSE329545","cross_references":{"GSM":["GSM9706191","GSM9706192","GSM9706193","GSM9706194","GSM9706190","GSM9706210","GSM9706199","GSM9706211","GSM9706212","GSM9706213","GSM9706195","GSM9706196","GSM9706197","GSM9706198","GSM9706218","GSM9706219","GSM9706214","GSM9706215","GSM9706216","GSM9706217","GSM9706181","GSM9706182","GSM9706183","GSM9706188","GSM9706221","GSM9706222","GSM9706200","GSM9706189","GSM9706223","GSM9706201","GSM9706202","GSM9706224","GSM9706184","GSM9706185","GSM9706186","GSM9706187","GSM9706220","GSM9706207","GSM9706208","GSM9706209","GSM9706225","GSM9706203","GSM9706226","GSM9706204","GSM9706227","GSM9706205","GSM9706228","GSM9706206"],"GPL":["34284"],"GSE":["329545"],"taxon":["Homo sapiens"]}}