IFNL4

id: K9M1U5
gene_symbol: IFNL4
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Interferon lambda-4 (IFNL4) is a type III interferon (IFN-lambda family) that triggers
  antiviral responses by activating the JAK-STAT signaling pathway. IFNL4 is encoded
  upstream of IFNL3 and was discovered in association with hepatitis C virus (HCV)
  clearance. A common dinucleotide polymorphism (ss469415590 TT/ΔG) creates a frameshift
  that either produces functional IFNL4 protein or a pseudogene. Paradoxically, the
  allele producing functional IFNL4 (ΔG) is associated with IMPAIRED HCV clearance,
  while the inactive TT allele correlates with better outcomes. IFNL4 signals through
  the type III interferon receptor complex (IFNLR1/IL10RB), activating JAK1/TYK2
  kinases which phosphorylate STAT1 and STAT2. The protein is secreted and induces
  interferon-stimulated genes (ISGs). Four isoforms exist but only isoform 1 (p179)
  is functionally active.
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: >-
        Phylogenetically inferred annotation appropriate for a type III interferon.
        IFNL4 triggers innate immune responses through ISG induction. Core function
        of all interferons.
      action: ACCEPT
  - term:
      id: GO:0051607
      label: defense response to virus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Phylogenetically inferred annotation. IFNL4 is part of the antiviral
        defense system - type III interferons are induced by viral infection and
        trigger antiviral gene expression. Core function.
      action: ACCEPT
  - term:
      id: GO:0005102
      label: signaling receptor binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Correct but general annotation. IFNL4 binds the type III interferon receptor
        complex (IFNLR1/IL10RB). More specific term cytokine activity (GO:0005125)
        is more appropriate.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Correct localization. IFNL4 is a secreted cytokine that acts in the
        extracellular space to bind cell surface receptors. Supported by experimental
        evidence (PMID:23291588).
      action: ACCEPT
# IEA annotations - automated methods
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Core molecular function. IFNL4 is a type III interferon (cytokine) that
        binds to the IFNLR1/IL10RB receptor complex and activates downstream
        signaling. Primary MF term for this gene.
      action: ACCEPT
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        General location term. IFNL4 is secreted. More specific term (extracellular
        space) is also annotated. Keep as supporting annotation.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Duplicates IBA and IDA annotations for same term. Consistent with secreted
        nature of IFNL4. Maintain consistent action.
      action: ACCEPT
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        Based on UniProt subcellular location. IFNL4 passes through cytoplasm
        during secretion. Some cytoplasmic localization observed (PMID:23291588).
        Consistent with IDA annotation.
      action: ACCEPT
  - term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IFNL4 triggers JAK-STAT signaling via its receptor complex. However, this
        term describes the pathway IFNL4 initiates as a ligand, not a process it
        directly participates in enzymatically. The annotation is reasonable but
        imprecise - IFNL4's role is as the cytokine that activates the pathway.
      action: KEEP_AS_NON_CORE
  - term:
      id: GO:0050778
      label: positive regulation of immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Correct annotation. IFNL4 induces interferon-stimulated genes and enhances
        immune response. Core function of type III interferons.
      action: ACCEPT
  - term:
      id: GO:0051607
      label: defense response to virus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicates IBA annotation for same term. Automated annotation consistent
        with IFNL4's antiviral function. Maintain consistent action.
      action: ACCEPT
# NAS annotations - non-traceable author statements
  - term:
      id: GO:0038196
      label: type III interferon-mediated signaling pathway
    evidence_type: NAS
    original_reference_id: PMID:30936491
    review:
      summary: >-
        Core biological process. IFNL4 is a type III interferon that signals through
        this pathway. This is the most specific and appropriate pathway term for
        IFNL4 function.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:30936491
          supporting_text: 2019 Apr 1. Decoding type I and III interferon 
            signalling during viral infection.
  - term:
      id: GO:0098586
      label: cellular response to virus
    evidence_type: NAS
    original_reference_id: PMID:30936491
    review:
      summary: >-
        Correct annotation. IFNL4 expression is induced by viral infection and
        participates in the cellular antiviral response. Supported by literature
        on HCV infection.
      action: ACCEPT
# IDA annotations - direct experimental assay
      supported_by:
        - reference_id: PMID:30936491
          supporting_text: 2019 Apr 1. Decoding type I and III interferon 
            signalling during viral infection.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IDA
    original_reference_id: PMID:23291588
    review:
      summary: >-
        Experimentally validated localization. PMID:23291588 shows IFNL4 is secreted.
        Core localization for a secreted cytokine.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:23291588
          supporting_text: A variant upstream of IFNL3 (IL28B) creating a new 
            interferon gene IFNL4 is associated with impaired clearance of 
            hepatitis C virus.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:23291588
    review:
      summary: >-
        Experimentally validated. Cytoplasmic localization observed, likely reflecting
        the secretory pathway or intracellular pool before secretion.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:23291588
          supporting_text: A variant upstream of IFNL3 (IL28B) creating a new 
            interferon gene IFNL4 is associated with impaired clearance of 
            hepatitis C virus.
  - term:
      id: GO:0007260
      label: tyrosine phosphorylation of STAT protein
    evidence_type: IDA
    original_reference_id: PMID:23291588
    review:
      summary: >-
        OVER-ANNOTATION: IFNL4 is a type III interferon (cytokine) that INDUCES STAT
        phosphorylation via the JAK-STAT signaling pathway, but does NOT catalyze
        the
        phosphorylation reaction itself. PMID:23291588 states "Transient overexpression
        of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation"
        -
        the interferon triggers downstream JAK kinases to phosphorylate STAT proteins.
        IFNL4 has no kinase activity (it is a secreted cytokine). The appropriate
        term
        is GO:0042531 "positive regulation of tyrosine phosphorylation of STAT protein"
        which correctly describes the regulatory role.
      action: MODIFY
      proposed_replacement_terms:
        - id: GO:0042531
          label: positive regulation of tyrosine phosphorylation of STAT protein
# IMP annotations - mutant phenotype
      supported_by:
        - reference_id: PMID:23291588
          supporting_text: A variant upstream of IFNL3 (IL28B) creating a new 
            interferon gene IFNL4 is associated with impaired clearance of 
            hepatitis C virus.
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IMP
    original_reference_id: PMID:23291588
    review:
      summary: >-
        Duplicates IEA annotation. Experimental evidence confirms cytokine activity
        -
        IFNL4 induces STAT phosphorylation and ISG expression. Core molecular function.
        Maintain consistent action.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:23291588
          supporting_text: A variant upstream of IFNL3 (IL28B) creating a new 
            interferon gene IFNL4 is associated with impaired clearance of 
            hepatitis C virus.
  - term:
      id: GO:0051607
      label: defense response to virus
    evidence_type: IMP
    original_reference_id: PMID:23291588
    review:
      summary: >-
        Duplicates IBA/IEA annotations. Experimental evidence from PMID:23291588
        confirms IFNL4 induces antiviral response. Maintain consistent action.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:23291588
          supporting_text: A variant upstream of IFNL3 (IL28B) creating a new 
            interferon gene IFNL4 is associated with impaired clearance of 
            hepatitis C virus.
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
core_functions:
  - molecular_function:
      id: GO:0005125
      label: cytokine activity
    description: >-
      IFNL4 functions as a type III interferon cytokine, binding to the IFNLR1/IL10RB
      receptor complex on target cells to activate the JAK1/TYK2-STAT1/STAT2 signaling
      pathway and induce interferon-stimulated genes (ISGs).
    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:0005615
        label: extracellular space
      - id: GO:0005737
        label: cytoplasm