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IL17F (interleukin 17F)

Written2013-09Seon Hee Chang
Department of Immunology, Center for Inflammation, Cancer, MD Anderson Cancer Center, Houston, TX, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)IL-17F
ML-1
ML1
Other aliasCANDF6
HGNC (Hugo) IL17F
LocusID (NCBI) 112744
Atlas_Id 42935
Location 6p12.2  [Link to chromosome band 6p12]
Location_base_pair Starts at 52236686 and ends at 52244500 bp from pter ( according to hg19-Feb_2009)  [Mapping IL17F.png]
Local_order Centromere - PKHD1 (polycystic kidney and hepatic diseases 1) - MIR206 (microRNA 206) - MIR133B (microRNA 133b) - IL17A (interleukin 17) - IL17F - SLC25A20P1 (solute carrier family 25, member 20 pseudogene 1) - MCM3 (minichromosome maintenance complex component 3) - Telomere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
USP38 (4q31.21) / IL17F (6p12.2)

DNA/RNA

 
  IL17F gene. The IL17F gene spans a region of 7.86 kb composed of the three exons (untranslated region (UTR), light blue; coding region, red) and two introns (green). Exons 1, 2, and 3 are 141 bp (108 bp 5' UTR plus 33 bp coding region), 221 bp (all coding region), and 488 bp (238 bp coding region plus 250 bp 3' UTR) in length, respectively. The two introns are 5446 bp and 1561 bp in length, respectively.
Description The gene spans a region of 7857 bases and the coding part is divided into three exons.
Tránsgription The 492-nucleotide transcript encodes a protein of 163 amino acid residues. The first and last exons are partially untranslated.
Pseudogene None described so far.

Protein

 
  Crystal structure of IL-17F at 2.85 A resomution. Adapted from PDB (access number: 1JPY).
Description Each IL-17F monomer forms homodimer with another IL-17F or heteromer with IL-17A (Chang and Dong, 2007; Wright et al., 2007). Calculated molecular weight of IL-17F monomer is a 15-kD. In non-reducing SDS-PAGE gel, IL-17F homodimer runs between 35 to 50kD depending on the level of glycosylation (Wright et al., 2007).
 
  IL-17F protein. IL-17F protein (163 amino acids) is composed of a signal peptide (orange, 30 amino acids) and a mature peptide (blue, 133 amino acids). Four conserved cysteine residues form intra-chain disulfide bonds (Cys102/Cys152 and Cys107/Cys154). Other two cysteines (Cys47 and Cys137) participate in homodimer formation via inter-chain disulfide bonds (Hymowitz et al., 2001). There is an intersubunit disulfide linkage between Cys47 from IL-17F and Cys129 from IL-17A. The presence of another intersubunit disulfide bond between Cys137 (IL-17F) and Cys33 (IL-17A) was also reported (Wright et al., 2007).
Expression Compared to IL-17 expression, IL-17F was detected more broadly in different tissues (Kawaguchi et al., 2001). In lymphoid lineages, IL-17F expression is tightly regulated. Results from IL-17FRFP reporter mouse or intracellular cytokine staining of IL-17F indicate that differentiated CD4 helper T cell Th17 cells, lamina propria CD4 T cells, memory CD4 T cells, γδ T cells, iNKT cells, and innate lymphoid cells (ILC3) produce IL-17F (Cua and Tato, 2010; Pantelyushin et al., 2012; Yang et al., 2008b). Regulation of IL-17F closely resembles its homologous protein IL-17A. In addition to TCR stimulation, TGFβ, IL-6, IL-23 and IL-1β are necessary to shape naïve CD4 T cells to Th17 cells. Transcription factors STAT3 and RORγτ are essential for production of IL-17F as well as IL-17 (Martinez et al., 2008; Peters et al., 2011; Zhou and Littman, 2009). IL-17F expression by either ILC3 or γδ T is induced by IL-1β or IL-23 (Geremia et al., 2011; Sutton et al., 2009). While IL-17A production from iNKT cells is independent from IL-6 (Doisne et al., 2009) and required TGFβ and IL-1β (Monteiro et al., 2013), it is not clear whether IL-17F expression is regulated by the same cytokines in iNKT cells.
Distinctive regulatory pathways of IL-17F have been reported. Itk-mediated activation of NFATc1 upon TCR stimulation induces IL-17A but not IL-17F (Gomez-Rodriguez et al., 2009). Conserved noncoding sites (CNS)2 in the Il17-Il17f locus is required for IL-17A expression but partially required for IL-17F expression, indicating other regulatory elements are involved in the regulation of IL-17F expression (Wang et al., 2012). While signaling pathways or transcription factors governing γδ T cells (Korn and Petermann, 2012) or iNKT cells producing IL-17A (Engel et al., 2012; Watarai et al., 2012) were reported before, the specific regulatory pathways of IL-17F in these innate cells remain elusive.
IL-17A production is restricted to lymphoid lineages but IL-17F was reported to be expressed by non-lymphoid cells that do not express IL-17A, such as human colonic epithelial cells (Tong et al., 2012). IL-17F is produced by non-T, non-B innate immune cells and mouse colonic epithelial cells in response to infection with C. rodentium (Ishigame et al., 2009). IL-17F is predominantly expressed in bronchial epithelial cells in addition to the infiltrating inflammatory cells upon asthma induction (Suzuki et al., 2007).
Localisation IL-17F is a secreted protein.
Function IL-17F exerts its biological effects through the IL-17RA/RC signaling complex. While the expression of IL-17RA is universal, IL-17RC expression is largely restricted to epithelial cells, fibroblasts and other stromal cells. IL-17RA/RC complex recruits an adaptor molecule, Act1, for signaling (Chang et al., 2006; Qian et al., 2007). Upon binding IL-17F, IL-17RA/RC can activate NF-kB and MAPK pathways. IL-17F shares the receptor complex with IL-17A homodimer and IL-17A/F heterodimer. They do not compete for the binding to the receptor complex since these cytokines together in the culture resulted in additive effects on production of pro-inflammatory molecules. Binding affinity of IL-17F to IL-17RA is weaker compared to IL-17F binding to IL-17RC (Kuestner et al., 2007). A crystal structure revealed that IL-17RA bound to IL-17F in a 1:2 stoichiometry and IL-17RA - IL-17F complex prefers to form heterodimers with a second receptor, IL-17RC, possibly due to steric hindrance (Ely et al., 2009).
Homology IL-17A is the most homologues protein.

Mutations

Note Familial chronic mucocutaneous candidiasis-6 (CANDF6) is caused by heterozygous ser65-to-leu mutation in the IL17F gene (Puel et al., 2011).
Chronic mucocutaneous candidiasis (CMC) is characterized by infections of the skin, nails, and oral and genital mucosae with Candida albicans, which is commensal in healthy individuals. S65L IL-17F behaves dominant-negative IL17F allele, which impairs the receptor binding and bioactivity of both IL-17F homodimers and IL-17A - IL-17F heterodimers.
A coding region variant (His161Arg) of IL-17F gene, possibly encoding an antagonist for IL-17F, has been linked to asthma patients in Japanese populations (Kawaguchi et al., 2006).

Implicated in

Note
  
Entity Host defense against infections
Note IL-17F expression has been detected in various types of infections. So far, IL-17F has been mainly involved in mucosal host defense mechanisms. IL-17F deficient mice are susceptible in C. rodentium infection and defective in producing β defensin during the infection (Ishigame et al., 2009). IL-17F is also required to protect the mice against mucocutaneous S. aureus infections (Ishigame et al., 2009).
  
  
Entity Intestinal inflammation
Note In acute colitis model using dextran sulfate sodium, IL-17F deficiency resulted in reduced colitis symptoms (Yang et al., 2008a). This phenotype is opposite to IL-17 deficiency, where IL-17 knockout mice developed more severe colitis. However, in chronic colitis using CD4 transfer system, pathology was mediated by redundant effects of IL-17A and IL-17F (Leppkes et al., 2009), suggesting therapeutic blocking of both IL-17A and IL-17F is likely to be required to suppress the inflammation in colon.
  
  
Entity Colon cancer
Note IL-17F deficiency resulted in increased colonic tumor numbers. IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues in this study (Tong et al., 2012).
  
  
Entity Autoimmune diseases
Note In experimental autoimmune encephalitis, IL-17F is not required for the initiation of the disease (Yang et al., 2008a) and may play a redundant role in promoting inflammation (Haak et al., 2009). IL-17F is not required to induce inflammation either in collagen induced arthritis model, or arthritis model using IL-1rn deficient mice (Ishigame et al., 2009).
  
  
Entity Lung inflammations
Note IL-17F has been detected in the lungs from asthma and COPD. IL-17F was detected in BALF of allergic patients (Kawaguchi et al., 2001) or bronchial epithelial cells after asthma induction (Suzuki et al., 2007). The role of IL-17F in allergic asthma has been argued. While several studies have shown that IL-17A and IL-17F are dispensable or negative regulator in eosinophilia of allergic asthma (Schnyder-Candrian et al., 2006; Suzukawa et al., 2012), asthmatic inflammation is heterogeneous. Steroid-resistant airway inflammation, airway remodeling, or airway hyperreactivity during asthmatic inflammation were reported to be dependent on Th17 or IL-17A (Kudo et al., 2012; Lajoie et al., 2010; McKinley et al., 2008; Pichavant et al., 2008). IL-17F, on the other hand, was required for neutrophil recruitment upon acute allergen challenge (Yang et al., 2008a).
  

Bibliography

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Citation

This paper should be referenced as such :
Chang, SH
IL17F (interleukin 17F)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(4):264-268.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IL17FID42935ch6p12.html


External links

Nomenclature
HGNC (Hugo)IL17F   16404
LRG (Locus Reference Genomic)LRG_356
Cards
AtlasIL17FID42935ch6p12
Entrez_Gene (NCBI)IL17F  112744  interleukin 17F
AliasesCANDF6; IL-17F; ML-1; ML1
GeneCards (Weizmann)IL17F
Ensembl hg19 (Hinxton)ENSG00000112116 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000112116 [Gene_View]  chr6:52236686-52244500 [Contig_View]  IL17F [Vega]
ICGC DataPortalENSG00000112116
TCGA cBioPortalIL17F
AceView (NCBI)IL17F
Genatlas (Paris)IL17F
WikiGenes112744
SOURCE (Princeton)IL17F
Genetics Home Reference (NIH)IL17F
Genomic and cartography
GoldenPath hg38 (UCSC)IL17F  -     chr6:52236686-52244500 -  6p12.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IL17F  -     6p12.2   [Description]    (hg19-Feb_2009)
EnsemblIL17F - 6p12.2 [CytoView hg19]  IL17F - 6p12.2 [CytoView hg38]
Mapping of homologs : NCBIIL17F [Mapview hg19]  IL17F [Mapview hg38]
OMIM606496   613956   
Gene and transcription
Genbank (Entrez)AF332389 AF384857 BC070124 JF305974
RefSeq transcript (Entrez)NM_052872
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)IL17F
Cluster EST : UnigeneHs.272295 [ NCBI ]
CGAP (NCI)Hs.272295
Alternative Splicing GalleryENSG00000112116
Gene ExpressionIL17F [ NCBI-GEO ]   IL17F [ EBI - ARRAY_EXPRESS ]   IL17F [ SEEK ]   IL17F [ MEM ]
Gene Expression Viewer (FireBrowse)IL17F [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)112744
GTEX Portal (Tissue expression)IL17F
Human Protein AtlasENSG00000112116-IL17F [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96PD4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96PD4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96PD4
Splice isoforms : SwissVarQ96PD4
PhosPhoSitePlusQ96PD4
Domains : Interpro (EBI)Cystine-knot_cytokine    IL-17_chr    IL-17_fam   
Domain families : Pfam (Sanger)IL17 (PF06083)   
Domain families : Pfam (NCBI)pfam06083   
Conserved Domain (NCBI)IL17F
DMDM Disease mutations112744
Blocks (Seattle)IL17F
PDB (SRS)1JPY    3JVF   
PDB (PDBSum)1JPY    3JVF   
PDB (IMB)1JPY    3JVF   
PDB (RSDB)1JPY    3JVF   
8a href=../extdef.html#SBKB TARGET=SBKB>Structural Biology KnowledgeBase1JPY    3JVF   
SCOP (Structural Classification of Proteins)1JPY    3JVF   
CATH (Classification of proteins structures)1JPY    3JVF   
SuperfamilyQ96PD4
Human Protein Atlas [tissue]ENSG00000112116-IL17F [tissue]
Peptide AtlasQ96PD4
HPRD16224
IPIIPI00791572   
Protein Interaction databases
DIP (DOE-UCLA)Q96PD4
IntAct (EBI)Q96PD4
FunCoupENSG00000112116
BioGRIDIL17F
STRING (EMBL)IL17F
ZODIACIL17F
Ontologies - Pathways
QuickGOQ96PD4
Ontology : AmiGOcytokine activity  cytokine receptor binding  protein binding  extracellular region  extracellular region  extracellular space  inflammatory response  negative regulation of angiogenesis  regulation of transforming growth factor beta receptor signaling pathway  cytokine binding  cytokine biosynthetic process  lymphotoxin A biosynthetic process  protein homodimerization activity  regulation of interleukin-2 biosynthetic process  regulation of interleukin-6 biosynthetic process  regulation of interleukin-8 biosynthetic process  regulation of granulocyte macrophage colony-stimulating factor biosynthetic process  positive regulation of transcription from RNA polymerase II promoter  cartilage development  positive regulation of cytokine production involved in inflammatory response  positive regulation of interleukin-6 secretion  
Ontology : EGO-EBIcytokine activity  cytokine receptor binding  protein binding  extracellular region  extracellular region  extracellular space  inflammatory response  negative regulation of angiogenesis  regulation of transforming growth factor beta receptor signaling pathway  cytokine binding  cytokine biosynthetic process  lymphotoxin A biosynthetic process  protein homodimerization activity  regulation of interleukin-2 biosynthetic process  regulation of interleukin-6 biosynthetic process  regulation of interleukin-8 biosynthetic process  regulation of granulocyte macrophage colony-stimulating factor biosynthetic process  positive regulation of transcription from RNA polymerase II promoter  cartilage development  positive regulation of cytokine production involved in inflammatory response  positive regulation of interleukin-6 secretion  
Pathways : KEGGInflammatory bowel disease (IBD)   
REACTOMEQ96PD4 [protein]
REACTOME PathwaysR-HSA-6785807 [pathway]   
NDEx NetworkIL17F
Atlas of Cancer Signalling NetworkIL17F
Wikipedia pathwaysIL17F
Orthology - Evolution
OrthoDB112744
GeneTree (enSembl)ENSG00000112116
Phylogenetic Trees/Animal Genes : TreeFamIL17F
HOVERGENQ96PD4
HOGENOMQ96PD4
Homologs : HomoloGeneIL17F
Homology/Alignments : Family Browser (UCSC)IL17F
Gene fusions - Rearrangements
Fusion : MitelmanUSP38/IL17F [4q31.21/6p12.2]  [t(4;6)(q31;p12)]  
Fusion: TCGA_MDACCUSP38 4q31.21 IL17F 6p12.2 BLCA
Tumor Fusion PortalIL17F
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIL17F [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IL17F
dbVarIL17F
ClinVarIL17F
1000_GenomesIL17F 
Exome Variant ServerIL17F
ExAC (Exome Aggregation Consortium)ENSG00000112116
GNOMAD BrowserENSG00000112116
Genetic variants : HAPMAP112744
Genomic Variants (DGV)IL17F [DGVbeta]
DECIPHERIL17F [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIL17F 
Mutations
ICGC Data PortalIL17F 
TCGA Data PortalIL17F 
Broad Tumor PortalIL17F
OASIS PortalIL17F [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIL17F  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIL17F
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch IL17F
DgiDB (Drug Gene Interaction Database)IL17F
DoCM (Curated mutations)IL17F (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IL17F (select a term)
intoGenIL17F
NCG5 (London)IL17F
Cancer3DIL17F(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606496    613956   
Orphanet432   
DisGeNETIL17F
MedgenIL17F
Genetic Testing Registry IL17F
NextProtQ96PD4 [Medical]
TSGene112744
GENETestsIL17F
Target ValidationIL17F
Huge Navigator IL17F [HugePedia]
snp3D : Map Gene to Disease112744
BioCentury BCIQIL17F
ClinGenIL17F
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD112744
Chemical/Pharm GKB GenePA29800
Clinical trialIL17F
Miscellaneous
canSAR (ICR)IL17F (select the gene name)
Probes
Litterature
PubMed146 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIL17F
EVEXIL17F
GoPubMedIL17F
iHOPIL17F
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Nov 21 14:53:11 CET 2017

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