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.
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The target described in the prompt—human IFNL4 encoding interferon lambda-4 (IFN-λ4), UniProt K9M1U5 (precursor; IFN-lambda family; IFN-lambda_sf/INF_lambda/IL28A-like domain)—is consistent with the literature and database-linked evidence: a 2023 interferon review explicitly lists UniProt K9M1U5 isoforms for IFN-λ4, and multiple sources place IFNL4 as the fourth member of the human type III interferon (IFN-λ) family discovered in 2013 from stimulated primary hepatocytes. (mertowska2023immunomodulatoryroleof pages 4-6, liu2024interferonlambdain pages 1-2)
To visualize the correct locus and functional variant used throughout human genetics literature, Figure 1 from O’Brien et al. schematizes the chromosome 19 IFNL locus and pinpoints the key functional dinucleotide variant rs368234815 (ΔG/TT) in IFNL4 exon 1. (obrien2014ifnλ4theparadoxical media fab7dc7f)
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. The human IFN-λ family includes IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. (mertowska2023immunomodulatoryroleof pages 4-6, liu2024interferonlambdain pages 1-2)
IFN-λ4 is described as a distinct IFN-λ family member, most similar to IFN-λ3 but with only ~29–30% amino acid identity in a foundational review, emphasizing that IFN-λ4 is not merely a minor variant of IFN-λ3. (obrien2014ifnλ4theparadoxical pages 3-5, obrien2014ifnλ4theparadoxical pages 1-2)
A defining concept for IFNL4 is that protein production is genetically controlled. A dinucleotide frameshift variant rs368234815 (ΔG/TT) in exon 1 determines whether a functional open reading frame exists:
- ΔG allele: creates an ORF → enables production of full-length IFN-λ4
- TT allele: disrupts the ORF → no functional IFN-λ4 protein
This genotype-to-protein “switch” is repeatedly emphasized across sources and is shown schematically in the cited figure. (obrien2014ifnλ4theparadoxical pages 2-3, mertowska2023immunomodulatoryroleof pages 4-6, obrien2014ifnλ4theparadoxical media fab7dc7f)
A commonly used GWAS marker in the region is rs12979860, located in intron 1 of IFNL4 and often in strong linkage disequilibrium with rs368234815, with LD patterns varying by ancestry (notably weaker LD in African ancestry populations). (obrien2014ifnλ4theparadoxical pages 2-3)
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. (obrien2014ifnλ4theparadoxical pages 3-5, liu2024interferonlambdain pages 1-2)
IFN-λs (including IFN-λ4) signal through a heterodimeric receptor complex consisting of:
- IFNLR1 (IFN-λR1; α-chain)
- IL10R2 (also referred to as IL-10R2/IL10RB; β-chain)
Ligand binding induces activation of receptor-associated kinases (classically JAK1 and TYK2) and downstream phosphorylation and activation of STAT1/STAT2, with IRF9 forming ISGF3, translocating to the nucleus and inducing ISGs via interferon-stimulated response elements (ISREs). (obrien2014ifnλ4theparadoxical pages 2-3, liu2024interferonlambdain pages 1-2)
A mechanistic study in human liver-derived cell lines directly tested IFNL3 vs IFNL4 signaling and concluded that IFNL4 responses depend exclusively on canonical receptor signaling:
- CRISPR/Cas9 knockout of IFNLR1 or IL10R2 abolished JAK–STAT activation/ISG responses to IFNLs.
- RNA-seq in receptor-deficient cells transfected with IFNL4 did not reveal an alternative signaling “signature,” arguing against IFNL4-specific receptor-independent signaling in this system.
- Non-tagged IFNL3 and IFNL4 induced highly similar transcriptomic responses.
These results position IFN-λ4 squarely in the canonical IFNLR1/IL10R2 → JAK–STAT → ISG pathway. (lunova2021expressionofinterferons pages 1-2, lunova2021expressionofinterferons pages 9-11)
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. (lunova2021expressionofinterferons pages 9-11)
A key feature separating type III from type I interferons is restricted receptor distribution: IFNLR1 expression is enriched in epithelial-lineage and barrier tissues (e.g., lung/intestine/liver), and IFN-λ is preferentially produced by epithelial cells, consistent with a specialized role in mucosal antiviral defense. (syedbasha2017interferonlambdamodulating pages 2-4, obrien2014ifnλ4theparadoxical pages 1-2, liu2024interferonlambdain pages 1-2)
This restricted responsiveness provides a mechanistic rationale for why IFN-λ4 (like other IFN-λs) is often discussed in the context of respiratory and gastrointestinal epithelium and hepatocytes rather than broad systemic leukocyte activity. (obrien2014ifnλ4theparadoxical pages 1-2, liu2024interferonlambdain pages 1-2)
IFNL4 genotype is historically one of the strongest host genetic predictors of HCV outcomes. The ΔG allele (IFN-λ4-producing) has been linked to:
- higher intrahepatic ISG expression
- impaired spontaneous and interferon-α–induced HCV clearance
This paradox—an antiviral cytokine genetically associated with worse viral clearance—remains a central interpretive theme in the IFNL4 literature. (lunova2021expressionofinterferons pages 1-2, obrien2014ifnλ4theparadoxical pages 3-5)
A 2024 narrative review on spontaneous HCV clearance reiterates that IFNL3/IFNL4 polymorphisms are among host genetic factors that can increase the odds of spontaneous clearance in some cohorts, while also emphasizing limitations (population-specific results; confounding; need for multivariable analyses). The review provides specific effect sizes for some IFNL3 SNPs (e.g., OR 2.68 and OR 3.0 in selected cohorts), but for IFNL4 it highlights the association more cautiously as requiring confirmation across populations. (rzymski2024likearolling pages 8-9)
Recent 2023–2024 work reflects heterogeneous signals for IFNL4 in SARS-CoV-2 infection:
- Pakistan cross-sectional study (Oct 2023; n=117): rs368234815 genotype differed between mild and severe COVID-19 (p=0.001), and nasopharyngeal IFNL4 mRNA was reported ~3.48-fold higher in severe vs mild disease (with IFNL3 showing the opposite trend in that cohort). (zahid2023associationofinterferon pages 1-2)
- Irish cohort study (Jul 2024; n=399; 319 genotyped): IFNL3 protein and IFNL3/IFNL4 SNPs were not associated with clinical outcome; the study’s key protective association was instead with lower/absent IFNL1/IFNL2 in severe outcomes, underscoring that IFNL4 genetics may not be a consistent predictor across cohorts/settings. (woods2024reducedifnl1andor pages 1-2)
Open Targets lists disease associations for IFNL4 including hepatitis C virus infection, chronic hepatitis C, liver disease, and cirrhosis, based on limited linked evidence counts in that resource (useful as a pointer rather than definitive causal proof). (OpenTargets Search: -IFNL4)
Recent 2023–2024 sources in the retrieved corpus emphasize:
1. Barrier-focused antiviral immunology: IFN-λ biology is framed as a front-line epithelial antiviral system with distinct receptor distribution compared with type I interferons. (liu2024interferonlambdain pages 1-2)
2. Variant-aware interpretation: IFNL4 is increasingly treated as a genotype-dependent cytokine system (presence/absence of protein) rather than a uniformly expressed cytokine gene. (mertowska2023immunomodulatoryroleof pages 4-6, woods2024reducedifnl1andor pages 1-2)
3. Infection-specific and cohort-specific signals: COVID-19 genetics results show that IFNL4 associations can appear in some cohorts (including local mucosal expression differences) and disappear in others, motivating larger and better-controlled studies. (zahid2023associationofinterferon pages 1-2, woods2024reducedifnl1andor pages 1-2)
The most mature “real-world” application of IFNL4 research has been host-genetic stratification in viral hepatitis, particularly to predict response to pegylated interferon-α + ribavirin (historical standard for HCV) and to interpret spontaneous clearance likelihood; IFNL4 functional status (rs368234815) and linked markers (rs12979860) are central to this literature. (obrien2014ifnλ4theparadoxical pages 3-5, obrien2014ifnλ4theparadoxical pages 2-3)
In the direct-acting antiviral (DAA) era, one mechanistic pilot study evaluating ultra-short sofosbuvir/daclatasvir treatment reported no evidence that treatment failure was associated with host IFNL4 genotype in that small study context, suggesting reduced clinical utility of IFNL4 genotype for predicting DAA response under those specific conditions. (rzymski2024likearolling pages 8-9)
A 2024 review highlights therapeutic interest in IFN-λ as an antiviral strategy at mucosal surfaces (with potential respiratory virus applications), but the retrieved evidence does not establish routine clinical implementation specifically for IFN-λ4 as a therapeutic ligand. Instead, translation has largely focused on IFN-λ biology broadly and other IFN-λ ligands in clinical development contexts. (liu2024interferonlambdain pages 1-2, obrien2014ifnλ4theparadoxical pages 1-2)
The following table consolidates the key functional annotation claims, supporting evidence, and the most relevant sources (with DOI URLs and publication dates).
| Topic | Key points | Supporting evidence with citation IDs | Key primary/review sources with DOI URL and publication month/year |
|---|---|---|---|
| Identity/definition | IFNL4 is the human gene encoding interferon lambda-4 (IFN-λ4), a type III interferon in the lambda interferon family; the gathered evidence explicitly links UniProt accession K9M1U5 to IFN-λ4 and notes that IFN-λ4 was identified in 2013 from poly(I:C)-stimulated primary human hepatocytes. | IFN-λ4 is a type III IFN and UniProt K9M1U5 isoform information is listed in a 2023 review; 2024 review places IFN-λ4 among the four human IFN-λ subtypes and notes 2013 discovery (mertowska2023immunomodulatoryroleof pages 4-6, liu2024interferonlambdain pages 1-2) | Mertowska et al., Int J Mol Sci (Jun 2023), https://doi.org/10.3390/ijms241210115; Liu et al., Front Immunol (Mar 2024), https://doi.org/10.3389/fimmu.2024.1338096 |
| Protein structure/isoforms | IFN-λ4 is a distinct IFN-λ family member, most similar to IFN-λ3 but sharing only ~29–30% amino-acid identity in the cited review; IFN-λ4 has four alternatively spliced isoforms, with UniProt K9M1U5 isoform entries noted in 2023 evidence. | Distinct family member with low identity to IFN-λ3; four alternatively spliced isoforms and UniProt-derived isoform entries reported (obrien2014ifnλ4theparadoxical pages 3-5, mertowska2023immunomodulatoryroleof pages 4-6) | O'Brien et al., J Interferon Cytokine Res (Nov 2014), https://doi.org/10.1089/jir.2013.0136; Mertowska et al., Int J Mol Sci (Jun 2023), https://doi.org/10.3390/ijms241210115 |
| Receptor & signaling | 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. CRISPR loss of IFNLR1 or IL10R2 abolished IFNL3/4 responses in liver cell models, supporting receptor-dependent canonical signaling and arguing against IFN-λ4-specific non-canonical signaling. | Canonical IFNLR1/IL10R2 signaling and JAK-STAT activation; IFNLR1 or IL10R2 knockout abolishes response; no evidence for IFN-λ4-specific non-canonical signaling in tested liver cell lines (lunova2021expressionofinterferons pages 1-2, lunova2021expressionofinterferons pages 14-16, lunova2021expressionofinterferons pages 9-11, obrien2014ifnλ4theparadoxical pages 3-5, obrien2014ifnλ4theparadoxical pages 2-3, liu2024interferonlambdain pages 1-2) | Lunova et al., Int J Mol Sci (Mar 2021), https://doi.org/10.3390/ijms22052560; O'Brien et al., J Interferon Cytokine Res (Nov 2014), https://doi.org/10.1089/jir.2013.0136; Liu et al., Front Immunol (Mar 2024), https://doi.org/10.3389/fimmu.2024.1338096 |
| Expression/localization | IFNLR1 expression is restricted relative to type I IFN receptors and is enriched in epithelial-lineage and mucosal/barrier tissues; cited sources note expression in lung, intestine, liver, kidney/stomach, and epithelial cells, explaining tissue-restricted IFN-λ4 activity. IFN-λs are preferentially produced by epithelial cells and act as front-line mucosal antiviral cytokines. | Restricted IFNLR1 expression in epithelial/mucosal tissues; epithelial-focused IFN-λ production/action; liver relevance noted in hepatocyte studies (lunova2021expressionofinterferons pages 1-2, syedbasha2017interferonlambdamodulating pages 2-4, novotny2025expressionandfunction pages 3-5, obrien2014ifnλ4theparadoxical pages 1-2, liu2024interferonlambdain pages 1-2) | Syedbasha & Egli, Front Immunol (Feb 2017), https://doi.org/10.3389/fimmu.2017.00119; Liu et al., Front Immunol (Mar 2024), https://doi.org/10.3389/fimmu.2024.1338096; Novotny & Meissner, FEBS Lett (Oct 2025), https://doi.org/10.1002/1873-3468.15041 |
| Genetics/variants | The key functional variant is rs368234815 (ΔG/TT) in exon 1: the ΔG allele creates the IFNL4 open reading frame and enables IFN-λ4 production, whereas the TT allele abolishes it. rs12979860 lies within intron 1 of IFNL4 and is often in strong linkage disequilibrium with rs368234815, though LD is weaker in Africans. Figure evidence specifically highlights chromosome 19 localization and the rs368234815 schematic. | Functional ΔG/TT frameshift controls IFN-λ4 production; rs12979860 linked marker with ancestry-dependent LD; figure depicts gene family and rs368234815 position (mertowska2023immunomodulatoryroleof pages 4-6, obrien2014ifnλ4theparadoxical pages 3-5, obrien2014ifnλ4theparadoxical pages 2-3, obrien2014ifnλ4theparadoxical media fab7dc7f) | O'Brien et al., J Interferon Cytokine Res (Nov 2014), https://doi.org/10.1089/jir.2013.0136; Mertowska et al., Int J Mol Sci (Jun 2023), https://doi.org/10.3390/ijms241210115 |
| Disease associations | IFNL4 genetics are strongly associated with HCV outcomes: the ΔG/IFNL4 genotype is linked to higher hepatic ISG expression and impaired spontaneous and interferon-α-induced HCV clearance, while IFNL locus SNPs remain strongly predictive of spontaneous HCV outcome in later reviews. Additional associations include liver disease/cirrhosis in Open Targets and a 2023 study reporting HHV-8-associated prostate cancer risk restricted to IFNL4-ΔG carriers. | HCV clearance/treatment-response association; higher hepatic ISGs with ΔG genotype; Open Targets liver disease links; HHV-8/prostate cancer signal in ΔG carriers (lunova2021expressionofinterferons pages 1-2, obrien2014ifnλ4theparadoxical pages 3-5, woods2024reducedifnl1andor pages 1-2, rzymski2024likearolling pages 8-9, OpenTargets Search: -IFNL4) | Lunova et al., Int J Mol Sci (Mar 2021), https://doi.org/10.3390/ijms22052560; O'Brien et al., J Interferon Cytokine Res (Nov 2014), https://doi.org/10.1089/jir.2013.0136; Rzymski et al., Viruses (Aug 2024), https://doi.org/10.3390/v16091386 |
| 2023-2024 developments | Recent literature emphasizes IFN-λ4 within broader mucosal antiviral immunity and human genetics. A 2023 Pakistani COVID-19 study (n=117) found the IFNL4 rs368234815 genotype differed between mild and severe cases (p=0.001), with IFNL4 mRNA 3.48-fold higher in severe disease; a 2024 Irish cohort study (n=399; 319 genotyped) found IFNL3/IFNL4 SNPs were not associated with COVID-19 outcome, illustrating context-dependent clinical signals. A 2024 HCV review highlights IFNL3/4 polymorphisms as contributors to spontaneous clearance but calls for larger, ethnically diverse multivariable analyses. | Quantitative 2023-2024 cohort data and updated interpretation of IFNL4 genetics across infections (zahid2023associationofinterferon pages 1-2, woods2024reducedifnl1andor pages 1-2, rzymski2024likearolling pages 8-9) | Zahid et al., Infect Drug Resist (Oct 2023), https://doi.org/10.2147/idr.s422095; Woods et al., Clin Exp Immunol (Jul 2024), https://doi.org/10.1093/cei/uxae047; Rzymski et al., Viruses (Aug 2024), https://doi.org/10.3390/v16091386 |
| Applications/implementations | Current real-world use is mainly genetic stratification/biomarker research rather than IFN-λ4-targeted therapy. IFNL4 genotypes have been used in studies of HCV spontaneous clearance and treatment-response prediction; however, mechanistic pilot data in the DAA era found no evidence that host IFNL4 genotype predicted failure of ultra-short sofosbuvir/daclatasvir first-line therapy. Broader IFN-λ therapeutic interest exists for antiviral therapy, but direct clinical implementation has focused more on other IFN-λ ligands than IFN-λ4 itself. | Biomarker/pharmacogenomic use in HCV; no strong support for IFNL4 genotype as predictor in one ultra-short DAA pilot; broader IFN-λ translational interest noted in recent reviews (obrien2014ifnλ4theparadoxical pages 1-2, rzymski2024likearolling pages 8-9) | O'Brien et al., J Interferon Cytokine Res (Nov 2014), https://doi.org/10.1089/jir.2013.0136; Rzymski et al., Viruses (Aug 2024), https://doi.org/10.3390/v16091386 |
Table: This table summarizes the functional annotation of human IFNL4 (UniProt K9M1U5), covering identity, signaling, localization, genetics, disease links, and recent 2023-2024 developments. It condenses the strongest gathered evidence into a citation-backed reference format for downstream report writing.
A schematic of the IFNL locus and the functional rs368234815 (ΔG/TT) variant controlling IFN-λ4 production is available in the cited figure. (obrien2014ifnλ4theparadoxical media fab7dc7f)
Although this report prioritizes 2023–2024 sources where available, several mechanistic details for IFN-λ4 (e.g., secretion efficiency, cell-type-specific regulation beyond receptor distribution, and explanations of the HCV paradox) are supported primarily in older foundational reviews and targeted experimental work in the retrieved corpus rather than in 2023–2024 primary mechanistic studies. (obrien2014ifnλ4theparadoxical pages 3-5, lunova2021expressionofinterferons pages 1-2)
References
(mertowska2023immunomodulatoryroleof pages 4-6): Paulina Mertowska, Konrad Smolak, Sebastian Mertowski, and Ewelina Grywalska. Immunomodulatory role of interferons in viral and bacterial infections. International Journal of Molecular Sciences, 24:10115, Jun 2023. URL: https://doi.org/10.3390/ijms241210115, doi:10.3390/ijms241210115. This article has 98 citations.
(liu2024interferonlambdain pages 1-2): Yong-Guang Liu, Su-Wei Jin, Shan-Shan Zhang, Tian-Ji Xia, Yong-Hong Liao, Rui-Le Pan, Ming-Zhu Yan, and Qi Chang. Interferon lambda in respiratory viral infection: immunomodulatory functions and antiviral effects in epithelium. Frontiers in Immunology, Mar 2024. URL: https://doi.org/10.3389/fimmu.2024.1338096, doi:10.3389/fimmu.2024.1338096. This article has 35 citations and is from a peer-reviewed journal.
(obrien2014ifnλ4theparadoxical media fab7dc7f): Thomas R. O'Brien, Ludmila Prokunina-Olsson, and Raymond P. Donnelly. Ifn-λ4: the paradoxical new member of the interferon lambda family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 34 11:829-38, Nov 2014. URL: https://doi.org/10.1089/jir.2013.0136, doi:10.1089/jir.2013.0136. This article has 216 citations.
(obrien2014ifnλ4theparadoxical pages 3-5): Thomas R. O'Brien, Ludmila Prokunina-Olsson, and Raymond P. Donnelly. Ifn-λ4: the paradoxical new member of the interferon lambda family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 34 11:829-38, Nov 2014. URL: https://doi.org/10.1089/jir.2013.0136, doi:10.1089/jir.2013.0136. This article has 216 citations.
(obrien2014ifnλ4theparadoxical pages 1-2): Thomas R. O'Brien, Ludmila Prokunina-Olsson, and Raymond P. Donnelly. Ifn-λ4: the paradoxical new member of the interferon lambda family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 34 11:829-38, Nov 2014. URL: https://doi.org/10.1089/jir.2013.0136, doi:10.1089/jir.2013.0136. This article has 216 citations.
(obrien2014ifnλ4theparadoxical pages 2-3): Thomas R. O'Brien, Ludmila Prokunina-Olsson, and Raymond P. Donnelly. Ifn-λ4: the paradoxical new member of the interferon lambda family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 34 11:829-38, Nov 2014. URL: https://doi.org/10.1089/jir.2013.0136, doi:10.1089/jir.2013.0136. This article has 216 citations.
(lunova2021expressionofinterferons pages 1-2): Mariia Lunova, Jan Kubovciak, Barbora Smolková, Mariia Uzhytchak, Kyra Michalova, Alexandr Dejneka, Pavel Strnad, Oleg Lunov, and Milan Jirsa. Expression of interferons lambda 3 and 4 induces identical response in human liver cell lines depending exclusively on canonical signaling. International Journal of Molecular Sciences, 22:2560, Mar 2021. URL: https://doi.org/10.3390/ijms22052560, doi:10.3390/ijms22052560. This article has 9 citations.
(lunova2021expressionofinterferons pages 9-11): Mariia Lunova, Jan Kubovciak, Barbora Smolková, Mariia Uzhytchak, Kyra Michalova, Alexandr Dejneka, Pavel Strnad, Oleg Lunov, and Milan Jirsa. Expression of interferons lambda 3 and 4 induces identical response in human liver cell lines depending exclusively on canonical signaling. International Journal of Molecular Sciences, 22:2560, Mar 2021. URL: https://doi.org/10.3390/ijms22052560, doi:10.3390/ijms22052560. This article has 9 citations.
(syedbasha2017interferonlambdamodulating pages 2-4): Mohammedyaseen Syedbasha and Adrian Egli. Interferon lambda: modulating immunity in infectious diseases. Frontiers in Immunology, Feb 2017. URL: https://doi.org/10.3389/fimmu.2017.00119, doi:10.3389/fimmu.2017.00119. This article has 205 citations and is from a peer-reviewed journal.
(rzymski2024likearolling pages 8-9): Piotr Rzymski, Michał Brzdęk, Krystyna Dobrowolska, Barbara Poniedziałek, Aleksandra Murawska-Ochab, Dorota Zarębska-Michaluk, and Robert Flisiak. Like a rolling stone? a review on spontaneous clearance of hepatitis c virus infection. Viruses, 16:1386, Aug 2024. URL: https://doi.org/10.3390/v16091386, doi:10.3390/v16091386. This article has 14 citations.
(zahid2023associationofinterferon pages 1-2): Warisha Zahid, Nida Farooqui, Nida Zahid, Khalid Ahmed, Muhammad Faraz Anwar, Syed Rizwan-ul-Hasan, Azhar Hussain, Antonio Sarría-Santamera, and Syed Hani Abidi. Association of interferon lambda 3 and 4 gene snps and their expression with covid-19 disease severity: a cross-sectional study. Infection and Drug Resistance, 16:6619-6628, Oct 2023. URL: https://doi.org/10.2147/idr.s422095, doi:10.2147/idr.s422095. This article has 14 citations and is from a peer-reviewed journal.
(woods2024reducedifnl1andor pages 1-2): Elena Woods, Adriana Mena, Sophie Sierpinska, Emily Carr, STTAR Bioresource, Richard Hagan, John Crowley, Colm Bergin, David Clark, Caroline Brophy, Derek Macallan, and Clair M Gardiner. Reduced ifnl1 and/or ifnl2, but not ifnl3 is associated with worse outcome in patients with covid-19. Clinical and Experimental Immunology, 218:300-307, Jul 2024. URL: https://doi.org/10.1093/cei/uxae047, doi:10.1093/cei/uxae047. This article has 1 citations and is from a peer-reviewed journal.
(OpenTargets Search: -IFNL4): Open Targets Query (-IFNL4, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(lunova2021expressionofinterferons pages 14-16): Mariia Lunova, Jan Kubovciak, Barbora Smolková, Mariia Uzhytchak, Kyra Michalova, Alexandr Dejneka, Pavel Strnad, Oleg Lunov, and Milan Jirsa. Expression of interferons lambda 3 and 4 induces identical response in human liver cell lines depending exclusively on canonical signaling. International Journal of Molecular Sciences, 22:2560, Mar 2021. URL: https://doi.org/10.3390/ijms22052560, doi:10.3390/ijms22052560. This article has 9 citations.
(novotny2025expressionandfunction pages 3-5): Laura A. Novotny and Eric G. Meissner. Expression and function of interferon lambda receptor 1 variants. FEBS Letters, Oct 2025. URL: https://doi.org/10.1002/1873-3468.15041, doi:10.1002/1873-3468.15041. This article has 7 citations and is from a peer-reviewed journal.
id: K9M1U5
gene_symbol: IFNL4
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
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.
existing_annotations:
# IBA annotations - phylogenetic inference
- term:
id: GO:0045087
label: innate immune response
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Innate immune response is an appropriate biological-process annotation for a type III
interferon that induces antiviral ISGs.
action: ACCEPT
reason: innate immune response is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051607
label: defense response to virus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Defense response to virus is a core process for IFNL4 through type III interferon
signaling and ISG induction.
action: ACCEPT
reason: defense response to virus is supported as part of the core type III interferon
cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:23291588
supporting_text: Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1
and STAT2 phosphorylation and the expression of interferon-stimulated genes.
- term:
id: GO:0005102
label: signaling receptor binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Signaling receptor binding is supported because IFN-lambda-4 acts through the
IFNLR1/IL10R2 receptor complex.
action: ACCEPT
reason: signaling receptor binding is supported as part of the core type III interferon
cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Extracellular space is appropriate for the secreted cytokine acting on cell-surface
IFN-lambda receptors.
action: ACCEPT
reason: extracellular space is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005125
label: cytokine activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Cytokine activity is the primary molecular-function term for IFNL4.
action: ACCEPT
reason: cytokine activity is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: Extracellular region is appropriate for secreted IFN-lambda-4 receptor engagement.
action: ACCEPT
reason: extracellular region is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Extracellular space is appropriate for the secreted cytokine acting on cell-surface
IFN-lambda receptors.
action: ACCEPT
reason: extracellular space is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: Cytoplasm is retained as non-core for intracellular/overexpression pools, but the
reviewed function is extracellular receptor engagement.
action: KEEP_AS_NON_CORE
reason: cytoplasm is observed or plausible but is secondary to extracellular cytokine
signaling.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: Cell surface receptor signaling pathway via JAK-STAT is the canonical pathway
activated by IFN-lambda-4.
action: ACCEPT
reason: cell surface receptor signaling pathway via JAK-STAT is supported as part of the core
type III interferon cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: These results position IFN-λ4 squarely in the **canonical IFNLR1/IL10R2 →
JAK–STAT → ISG** pathway.
- term:
id: GO:0050778
label: positive regulation of immune response
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: Positive regulation of immune response is supported by induction of antiviral ISGs
downstream of IFN-lambda receptor signaling.
action: ACCEPT
reason: positive regulation of immune response is supported as part of the core type III
interferon cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051607
label: defense response to virus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Defense response to virus is a core process for IFNL4 through type III interferon
signaling and ISG induction.
action: ACCEPT
reason: defense response to virus is supported as part of the core type III interferon
cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:23291588
supporting_text: Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1
and STAT2 phosphorylation and the expression of interferon-stimulated genes.
- term:
id: GO:0038196
label: type III interferon-mediated signaling pathway
evidence_type: NAS
original_reference_id: PMID:30936491
review:
summary: Type III interferon-mediated signaling pathway is the most specific pathway term for
IFNL4.
action: ACCEPT
reason: type III interferon-mediated signaling pathway is supported as part of the core type
III interferon cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: These results position IFN-λ4 squarely in the **canonical IFNLR1/IL10R2 →
JAK–STAT → ISG** pathway.
- term:
id: GO:0098586
label: cellular response to virus
evidence_type: NAS
original_reference_id: PMID:30936491
review:
summary: Cellular response to virus is supported through IFNL4 induction and IFN-stimulated
antiviral gene expression.
action: ACCEPT
reason: cellular response to virus is supported as part of the core type III interferon
cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:23291588
supporting_text: Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1
and STAT2 phosphorylation and the expression of interferon-stimulated genes.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:23291588
review:
summary: Extracellular space is appropriate for the secreted cytokine acting on cell-surface
IFN-lambda receptors.
action: ACCEPT
reason: extracellular space is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:23291588
review:
summary: Cytoplasm is retained as non-core for intracellular/overexpression pools, but the
reviewed function is extracellular receptor engagement.
action: KEEP_AS_NON_CORE
reason: cytoplasm is observed or plausible but is secondary to extracellular cytokine
signaling.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0007260
label: tyrosine phosphorylation of STAT protein
evidence_type: IDA
original_reference_id: PMID:23291588
review:
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.
action: MODIFY
reason: tyrosine phosphorylation of STAT protein overstates the role of IFNL4; the regulatory
STAT-phosphorylation term is more accurate.
proposed_replacement_terms:
- id: GO:0042531
label: positive regulation of tyrosine phosphorylation of STAT protein
supported_by:
- reference_id: PMID:23291588
supporting_text: Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1
and STAT2 phosphorylation and the expression of interferon-stimulated genes.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005125
label: cytokine activity
evidence_type: IMP
original_reference_id: PMID:23291588
review:
summary: Cytokine activity is the primary molecular-function term for IFNL4.
action: ACCEPT
reason: cytokine activity is supported as part of the core type III interferon cytokine
function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051607
label: defense response to virus
evidence_type: IMP
original_reference_id: PMID:23291588
review:
summary: Defense response to virus is a core process for IFNL4 through type III interferon
signaling and ISG induction.
action: ACCEPT
reason: defense response to virus is supported as part of the core type III interferon
cytokine function of IFNL4.
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:23291588
supporting_text: Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1
and STAT2 phosphorylation and the expression of interferon-stimulated genes.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
mapping, accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:23291588
title: A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated
with impaired clearance of hepatitis C virus.
findings:
- statement: IFNL4 was discovered as a novel type III interferon encoded upstream of IFNL3
- statement: A dinucleotide polymorphism (ss469415590 TT/ΔG) determines IFNL4 functionality
- statement: The ΔG allele produces functional IFNL4 protein associated with impaired HCV
clearance
- statement: Transient overexpression of IFNL4 induced STAT1 and STAT2 phosphorylation
- statement: IFNL4 induces expression of interferon-stimulated genes (ISGs)
- id: PMID:30936491
title: Decoding type I and III interferon signalling during viral infection.
findings:
- statement: Review of type I and III interferon signaling pathways
- id: file:human/IFNL4/IFNL4-deep-research-falcon.md
title: Falcon deep research synthesis for IFNL4
findings: []
core_functions:
- description: Secreted type III interferon cytokine activity that activates
IFNLR1/IL10R2-dependent JAK-STAT signaling and antiviral ISG expression.
molecular_function:
id: GO:0005125
label: cytokine activity
directly_involved_in:
- id: GO:0038196
label: type III interferon-mediated signaling pathway
- id: GO:0051607
label: defense response to virus
- id: GO:0045087
label: innate immune response
- id: GO:0050778
label: positive regulation of immune response
locations:
- id: GO:0005576
label: extracellular region
supported_by:
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/IFNL4/IFNL4-deep-research-falcon.md
supporting_text: 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.
- reference_id: PMID:23291588
supporting_text: Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and
STAT2 phosphorylation and the expression of interferon-stimulated genes.
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []