Interferon Lambda 3

IFNL3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3HHC
Identifiers
Aliases	IFNL3, IL-28B, IL28B, IL28C, Interleukin 28B, interferon, lambda 3, interferon lambda 3, IFN-lambda-3, IFN-lambda-4, IL-28C
External IDs	OMIM: 607402; MGI: 2450574; HomoloGene: 77540; GeneCards: IFNL3; OMA:IFNL3 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.2 Start 39,243,455 bp[1] End 39,245,250 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 A3 Start 28,222,261 bp[2] End 28,223,747 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle gonad superior frontal gyrus prefrontal cortex blood skin of abdomen placenta Temporal Lobe Amygdala urinary bladder Top expressed in thymus spleen More reference expression data BioGPS n/a
Gene ontology Molecular function cytokine activity signaling receptor binding Cellular component intracellular anatomical structure extracellular space extracellular region Biological process receptor signaling pathway via JAK-STAT negative regulation of viral genome replication positive regulation of immune response innate immune response defense response to virus regulation of T cell activation regulation of signaling receptor activity cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 282617 338374 Ensembl ENSG00000197110 ENSMUSG00000060747 UniProt Q8IZI9 Q8CGK6 RefSeq (mRNA) NM_172139 NM_001346937 NM_177396 RefSeq (protein) NP_001333866 NP_742151 NP_796370 Location (UCSC) Chr 19: 39.24 – 39.25 Mb Chr 7: 28.22 – 28.22 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interferon lambda 3 (gene symbol: IFNL3) encodes the IFNL3 protein. IFNL3 was formerly named IL28B, but the Human Genome Organization Gene Nomenclature Committee renamed this gene in 2013 while assigning a name to the then newly discovered IFNL4 gene.^[5] Together with IFNL1 (formerly IL29) and IFNL2 (formerly IL28A), these genes lie in a cluster on chromosomal region 19q13. IFNL3 shares ~96% amino-acid identity with IFNL2, ~80% identity with IFNL1 and ~30% identity with IFNL4.

Interferon lambda genes encode cytokines classified as type III interferons, which are distantly related to type I interferons and the IL-10 family. Type III interferons are induced by viral infection and interact with a heterodimeric class II cytokine receptor that consists of interleukin 10 receptor, beta (IL10RB) and interferon lambda receptor 1 (IFNLR1) to signal via the JAK-STAT anti-viral pathway. [provided by RefSeq, Jul 2008].

Hepatitis C

In 2009 (i.e., before the discovery of IFNL4), results from genome wide association studies (GWAS) indicated that single-nucleotide polymorphisms (SNPs) lying near IFNL3 (rs12979860, rs8099917 and others) were strongly associated with response to pegylated interferon-α and ribavirin treatment for chronic hepatitis C,^[6][7][8][9] as well as spontaneous clearance of hepatitis C (HCV) infection.^{[10][11][12][13]} The gene then known as IL28B (now IFNL3) was the closest known gene at the time, so these genetic variants were called “IL28B variants.” It was assumed that the observed associations reflected differences in the structure or regulation of that gene. However, discovery of IFNL4 revealed that the rs12979860 SNP is located within intron 1 of IFNL4, while rs8099917 lies in an intergenic region, but nearest to IFNL4.^[5]  The rs12979860 and rs8099917 SNPs are in high linkage disequilibrium with a variant of IFNL4 (IFNL4-ΔG/TT; rs368234815) that controls generation of the IFNL4 protein.^[5] IFNL4-ΔG/TT appears to be the functional polymorphism that accounts for GWAS associations of nearby SNPs with HCV clearance, and IFNL4-ΔG/TT was shown to have stronger statistical association with HCV clearance than that of rs12979860, especially in populations of African ancestry in which linkage disequilibrium between these variants is weaker than in other populations.^[5][14]

One possible functional variant in IFNL3 is the rs4803217 SNP, which lies in the 3’ untranslated regulatory region. Substitution of guanine for the ancestral thymine at this site increases IFNL3 mRNA expression by decreasing mRNA degradation and HCV-induced microRNA binding^[15] and changes the RNA structure.^[16][11] High linkage disequilibrium exists between rs4803217 and the IFNL4-ΔG/TT variant.^[5] rs4803217 has been shown to associate with HCV clearance,^[16] however, that association appears to stem from linkage disequilibrium with IFNL4-ΔG/TT rather than a direct functional effect of the rs4803217 SNP itself.

References

1. GRCh38: Ensembl release 89: ENSG00000197110 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000060747 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, et al. (February 2013). "A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus". Nature Genetics. 45 (2): 164–71. doi:10.1038/ng.2521. PMC 3793390. PMID 23291588.
6. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. (September 2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature. 461 (7262): 399–401. Bibcode:2009Natur.461..399G. doi:10.1038/nature08309. PMID 19684573. S2CID 1707096.
7. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. (October 2009). "IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy". Nature Genetics. 41 (10): 1100–4. doi:10.1038/ng.447. PMID 19749758. S2CID 21619093.
8. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. (October 2009). "Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C". Nature Genetics. 41 (10): 1105–9. doi:10.1038/ng.449. PMID 19749757. S2CID 20399078.
9. Muir AJ, Gong L, Johnson SG, Lee MT, Williams MS, Klein TE, et al. (February 2014). "Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α-based regimens". Clinical Pharmacology and Therapeutics. 95 (2): 141–6. doi:10.1038/clpt.2013.203. PMC 3904555. PMID 24096968.
10. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. (2009). "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus". Nature. 461 (7265): 798–801. Bibcode:2009Natur.461..798T. doi:10.1038/nature08463. PMC 3172006. PMID 19759533.
11. Salum GM, Dawood RM, Abd El-Meguid M, Ibrahim NE, Abdel Aziz AO, El Awady MK (September 2020). "Correlation between IL28B/TLR4 genetic variants and HCC development with/without DAAs treatment in chronic HCV patients". Genes & Diseases. 7 (3): 392–400. doi:10.1016/j.gendis.2019.05.004. PMC 7452484. PMID 32884993.
12. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. (October 2009). "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus". Nature. 461 (7265): 798–801. Bibcode:2009Natur.461..798T. doi:10.1038/nature08463. PMC 3172006. PMID 19759533.
13. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. (April 2010). "Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study". Gastroenterology. 138 (4): 1338–45, 1345.e1-7. doi:10.1053/j.gastro.2009.12.056. PMID 20060832. S2CID 25546833.
14. Lu YF, Goldstein DB, Urban TJ, Bradrick SS (February 2015). "Interferon-λ4 is a cell-autonomous type III interferon associated with pre-treatment hepatitis C virus burden". Virology. 476: 334–340. doi:10.1016/j.virol.2014.12.020. PMC 4494652. PMID 25577150.
15. McFarland AP, Horner SM, Jarret A, Joslyn RC, Bindewald E, Shapiro BA, et al. (January 2014). "The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs". Nature Immunology. 15 (1): 72–9. doi:10.1038/ni.2758. PMC 4183367. PMID 24241692.
16. Lu YF, Mauger DM, Goldstein DB, Urban TJ, Weeks KM, Bradrick SS (November 2015). "IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance". Scientific Reports. 5: 16037. Bibcode:2015NatSR...516037L. doi:10.1038/srep16037. PMC 4631997. PMID 26531896.

Further reading

• Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. (January 2003). "IL-28, IL-29 and their class II cytokine receptor IL-28R". Nature Immunology. 4 (1): 63–8. doi:10.1038/ni873. PMID 12469119. S2CID 35764259.
• Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. (January 2003). "IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex". Nature Immunology. 4 (1): 69–77. doi:10.1038/ni875. PMID 12483210. S2CID 2734534.
• Li M, He S (April 2006). "Purification and characterization of recombinant human interleukin-29 expressed in Escherichia coli". Journal of Biotechnology. 122 (3): 334–40. doi:10.1016/j.jbiotec.2005.11.019. PMID 16413080.
• Mennechet FJ, Uzé G (June 2006). "Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells". Blood. 107 (11): 4417–23. doi:10.1182/blood-2005-10-4129. PMID 16478884.
• Li MC, Wang HY, Wang HY, Li T, He SH (April 2006). "Liposome-mediated IL-28 and IL-29 expression in A549 cells and anti-viral effect of IL-28 and IL-29 on WISH cells". Acta Pharmacologica Sinica. 27 (4): 453–9. doi:10.1111/j.1745-7254.2006.00292.x. PMID 16539846.
• Lasfar A, Lewis-Antes A, Smirnov SV, Anantha S, Abushahba W, Tian B, et al. (April 2006). "Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma". Cancer Research. 66 (8): 4468–77. doi:10.1158/0008-5472.CAN-05-3653. PMID 16618774.
• Dellgren C, Gad HH, Hamming OJ, Melchjorsen J, Hartmann R (March 2009). "Human interferon-lambda3 is a potent member of the type III interferon family". Genes and Immunity. 10 (2): 125–31. doi:10.1038/gene.2008.87. PMID 18987645.
• Li M, Liu X, Zhou Y, Su SB (July 2009). "Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses". Journal of Leukocyte Biology. 86 (1): 23–32. doi:10.1189/jlb.1208761. PMID 19304895. S2CID 37741272.
• Gad HH, Dellgren C, Hamming OJ, Vends S, Paludan SR, Hartmann R (July 2009). "Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family". The Journal of Biological Chemistry. 284 (31): 20869–75. doi:10.1074/jbc.M109.002923. PMC 2742852. PMID 19457860.
• Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. (September 2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature. 461 (7262): 399–401. Bibcode:2009Natur.461..399G. doi:10.1038/nature08309. PMID 19684573. S2CID 1707096.