IFNL4 encodes interferon lambda-4, a secreted type III interferon cytokine. Functional IFN-lambda-4 binds the IFNLR1/IL10R2 receptor complex, activates canonical JAK1/TYK2-STAT1/STAT2-ISGF3 signaling, and induces interferon-stimulated genes that contribute to antiviral innate immunity at epithelial and hepatic barrier sites. Human rs368234815 controls production of the IFN-lambda-4 open reading frame, and the producing allele is paradoxically associated with impaired HCV clearance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Innate immune response is an appropriate biological-process annotation for a type III interferon that induces antiviral ISGs. Reason: innate immune response is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Type III interferons (**IFN-λs**) are antiviral cytokines that induce an antiviral transcriptional program via **interferon-stimulated genes (ISGs)** and are especially important at epithelial/mucosal barrier surfaces. file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 signals through the canonical heterodimeric IFN-λ receptor composed of IFNLR1 and IL10R2/IL10RB, activating JAK1/TYK2, STAT1/STAT2, ISGF3, ISRE-dependent transcription, and ISG induction. |
| GO:0051607 defense response to virus | IBA GO_REF:0000033 | ACCEPT | Summary: Defense response to virus is a core process for IFNL4 through type III interferon signaling and ISG induction. Reason: defense response to virus is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Type III interferons (**IFN-λs**) are antiviral cytokines that induce an antiviral transcriptional program via **interferon-stimulated genes (ISGs)** and are especially important at epithelial/mucosal barrier surfaces. file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. PMID:23291588 Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. |
| GO:0005102 signaling receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Signaling receptor binding is supported because IFN-lambda-4 acts through the IFNLR1/IL10R2 receptor complex. Reason: signaling receptor binding is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 signals through the canonical heterodimeric IFN-λ receptor composed of IFNLR1 and IL10R2/IL10RB, activating JAK1/TYK2, STAT1/STAT2, ISGF3, ISRE-dependent transcription, and ISG induction. |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: Extracellular space is appropriate for the secreted cytokine acting on cell-surface IFN-lambda receptors. Reason: extracellular space is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. file:human/IFNL4/IFNL4-deep-research-falcon.md As a cytokine, IFN-λ4’s primary site of action is **extracellular receptor engagement** at the plasma membrane of responsive cells expressing IFNLR1/IL10R2; the liver cell work also tested intracellular/cytosolic expression forms and did not support a distinct intracellular signaling mechanism that bypasses IFNLR1/IL10R2 in their models. |
| GO:0005125 cytokine activity | IEA GO_REF:0000120 | ACCEPT | Summary: Cytokine activity is the primary molecular-function term for IFNL4. Reason: cytokine activity is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 is best annotated as a **type III interferon cytokine** whose primary molecular function is to activate **IFNLR1/IL10R2** and drive **canonical JAK–STAT/ISGF3** signaling to induce ISGs, rather than catalyzing a biochemical reaction or transporting substrates. file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Extracellular region is appropriate for secreted IFN-lambda-4 receptor engagement. Reason: extracellular region is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. file:human/IFNL4/IFNL4-deep-research-falcon.md As a cytokine, IFN-λ4’s primary site of action is **extracellular receptor engagement** at the plasma membrane of responsive cells expressing IFNLR1/IL10R2; the liver cell work also tested intracellular/cytosolic expression forms and did not support a distinct intracellular signaling mechanism that bypasses IFNLR1/IL10R2 in their models. |
| GO:0005615 extracellular space | IEA GO_REF:0000043 | ACCEPT | Summary: Extracellular space is appropriate for the secreted cytokine acting on cell-surface IFN-lambda receptors. Reason: extracellular space is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. file:human/IFNL4/IFNL4-deep-research-falcon.md As a cytokine, IFN-λ4’s primary site of action is **extracellular receptor engagement** at the plasma membrane of responsive cells expressing IFNLR1/IL10R2; the liver cell work also tested intracellular/cytosolic expression forms and did not support a distinct intracellular signaling mechanism that bypasses IFNLR1/IL10R2 in their models. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm is retained as non-core for intracellular/overexpression pools, but the reviewed function is extracellular receptor engagement. Reason: cytoplasm is observed or plausible but is secondary to extracellular cytokine signaling. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md As a cytokine, IFN-λ4’s primary site of action is **extracellular receptor engagement** at the plasma membrane of responsive cells expressing IFNLR1/IL10R2; the liver cell work also tested intracellular/cytosolic expression forms and did not support a distinct intracellular signaling mechanism that bypasses IFNLR1/IL10R2 in their models. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IEA GO_REF:0000002 | ACCEPT | Summary: Cell surface receptor signaling pathway via JAK-STAT is the canonical pathway activated by IFN-lambda-4. Reason: cell surface receptor signaling pathway via JAK-STAT is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 signals through the canonical heterodimeric IFN-λ receptor composed of IFNLR1 and IL10R2/IL10RB, activating JAK1/TYK2, STAT1/STAT2, ISGF3, ISRE-dependent transcription, and ISG induction. file:human/IFNL4/IFNL4-deep-research-falcon.md These results position IFN-λ4 squarely in the **canonical IFNLR1/IL10R2 → JAK–STAT → ISG** pathway. |
| GO:0050778 positive regulation of immune response | IEA GO_REF:0000002 | ACCEPT | Summary: Positive regulation of immune response is supported by induction of antiviral ISGs downstream of IFN-lambda receptor signaling. Reason: positive regulation of immune response is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Type III interferons (**IFN-λs**) are antiviral cytokines that induce an antiviral transcriptional program via **interferon-stimulated genes (ISGs)** and are especially important at epithelial/mucosal barrier surfaces. file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 signals through the canonical heterodimeric IFN-λ receptor composed of IFNLR1 and IL10R2/IL10RB, activating JAK1/TYK2, STAT1/STAT2, ISGF3, ISRE-dependent transcription, and ISG induction. |
| GO:0051607 defense response to virus | IEA GO_REF:0000120 | ACCEPT | Summary: Defense response to virus is a core process for IFNL4 through type III interferon signaling and ISG induction. Reason: defense response to virus is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Type III interferons (**IFN-λs**) are antiviral cytokines that induce an antiviral transcriptional program via **interferon-stimulated genes (ISGs)** and are especially important at epithelial/mucosal barrier surfaces. file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. PMID:23291588 Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. |
| GO:0038196 type III interferon-mediated signaling pathway | NAS PMID:30936491 Decoding type I and III interferon signalling during viral i... | ACCEPT | Summary: Type III interferon-mediated signaling pathway is the most specific pathway term for IFNL4. Reason: type III interferon-mediated signaling pathway is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. file:human/IFNL4/IFNL4-deep-research-falcon.md These results position IFN-λ4 squarely in the **canonical IFNLR1/IL10R2 → JAK–STAT → ISG** pathway. |
| GO:0098586 cellular response to virus | NAS PMID:30936491 Decoding type I and III interferon signalling during viral i... | ACCEPT | Summary: Cellular response to virus is supported through IFNL4 induction and IFN-stimulated antiviral gene expression. Reason: cellular response to virus is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Type III interferons (**IFN-λs**) are antiviral cytokines that induce an antiviral transcriptional program via **interferon-stimulated genes (ISGs)** and are especially important at epithelial/mucosal barrier surfaces. PMID:23291588 Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. |
| GO:0005615 extracellular space | IDA PMID:23291588 A variant upstream of IFNL3 (IL28B) creating a new interfero... | ACCEPT | Summary: Extracellular space is appropriate for the secreted cytokine acting on cell-surface IFN-lambda receptors. Reason: extracellular space is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. file:human/IFNL4/IFNL4-deep-research-falcon.md As a cytokine, IFN-λ4’s primary site of action is **extracellular receptor engagement** at the plasma membrane of responsive cells expressing IFNLR1/IL10R2; the liver cell work also tested intracellular/cytosolic expression forms and did not support a distinct intracellular signaling mechanism that bypasses IFNLR1/IL10R2 in their models. |
| GO:0005737 cytoplasm | IDA PMID:23291588 A variant upstream of IFNL3 (IL28B) creating a new interfero... | KEEP AS NON CORE | Summary: Cytoplasm is retained as non-core for intracellular/overexpression pools, but the reviewed function is extracellular receptor engagement. Reason: cytoplasm is observed or plausible but is secondary to extracellular cytokine signaling. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md As a cytokine, IFN-λ4’s primary site of action is **extracellular receptor engagement** at the plasma membrane of responsive cells expressing IFNLR1/IL10R2; the liver cell work also tested intracellular/cytosolic expression forms and did not support a distinct intracellular signaling mechanism that bypasses IFNLR1/IL10R2 in their models. |
| GO:0007260 tyrosine phosphorylation of STAT protein | IDA PMID:23291588 A variant upstream of IFNL3 (IL28B) creating a new interfero... | MODIFY | Summary: IFNL4 induces STAT1/STAT2 phosphorylation through receptor-associated JAK kinases; it is not itself a kinase and should be annotated to the regulatory term. Reason: tyrosine phosphorylation of STAT protein overstates the role of IFNL4; the regulatory STAT-phosphorylation term is more accurate. Proposed replacements: positive regulation of tyrosine phosphorylation of STAT protein Supporting Evidence: PMID:23291588 Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 signals through the canonical heterodimeric IFN-λ receptor composed of IFNLR1 and IL10R2/IL10RB, activating JAK1/TYK2, STAT1/STAT2, ISGF3, ISRE-dependent transcription, and ISG induction. |
| GO:0005125 cytokine activity | IMP PMID:23291588 A variant upstream of IFNL3 (IL28B) creating a new interfero... | ACCEPT | Summary: Cytokine activity is the primary molecular-function term for IFNL4. Reason: cytokine activity is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md IFN-λ4 is best annotated as a **type III interferon cytokine** whose primary molecular function is to activate **IFNLR1/IL10R2** and drive **canonical JAK–STAT/ISGF3** signaling to induce ISGs, rather than catalyzing a biochemical reaction or transporting substrates. file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. |
| GO:0051607 defense response to virus | IMP PMID:23291588 A variant upstream of IFNL3 (IL28B) creating a new interfero... | ACCEPT | Summary: Defense response to virus is a core process for IFNL4 through type III interferon signaling and ISG induction. Reason: defense response to virus is supported as part of the core type III interferon cytokine function of IFNL4. Supporting Evidence: file:human/IFNL4/IFNL4-deep-research-falcon.md Type III interferons (**IFN-λs**) are antiviral cytokines that induce an antiviral transcriptional program via **interferon-stimulated genes (ISGs)** and are especially important at epithelial/mucosal barrier surfaces. file:human/IFNL4/IFNL4-deep-research-falcon.md Functionally, IFN-λ4 is a **secreted cytokine precursor** (with signal peptide/precursor concept in UniProt and IFN biology), whose primary molecular role is to bind the **type III interferon receptor** and trigger **canonical JAK–STAT signaling** to induce ISGs and antiviral defenses. PMID:23291588 Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. |
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