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43  structures 314  species 0  interactions 3941  sequences 30  architectures

Family: IRF (PF00605)

Summary: Interferon regulatory factor transcription factor

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This is the Wikipedia entry entitled "Interferon regulatory factors". More...

Interferon regulatory factors Edit Wikipedia article

Interferon regulatory factor transcription factor
PDB 1irf EBI.jpg
interferon regulatory factor-2 dna binding domain, nmr, minimized average structure

Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons (see regulation of gene expression).[1] Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a structure that binds specifically to the IRF-element (IRF-E) motifs, which is located upstream of the interferon genes.[2] Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system.[3] For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein.[2] The Kaposi sarcoma herpesvirus, KSHV,[4] is a cancer virus that encodes four different IRF-like genes;[5] including vIRF1,[6] which is a transforming oncoprotein that inhibits type 1 interferon activity.[7] In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA methylation.[8]

Role in IFN Signaling

IRFs primarily regulate type I IFNs in the host after pathogen invasion and are considered the crucial mediators of an antiviral response. Following a viral infection, pathogens are detected by Pattern Recognition Receptors (PRRs), including various types of Toll-like Receptors (TLR) and cytosolic PRRs, in the host cell.[3] The downstream signaling pathways from PRR activation phosphorylate ubiquitously expressed IRFs (IRF1, IRF3, and IRF7) through IRF kinases, such as TANK-binding kinase 1 (TBK1).[9] Phosphorylated IRFs are translocated to the nucleus where they bind to IRF-E motifs and activate the transcription of Type I IFNs. In addition to IFNs, IRF1 and IRF5 has been found to induce transcription of pro-inflammatory cytokines.

Some IFNs like IRF2 and IRF4 regulate the activation of IFNs and pro-inflammatory cytokines through inhibition. IRF2 contains a repressor region that downregulates expression of type I IFNs. IRF4 competes with IRF5, and inhibits its sustained activity.[3]

Role in Immune Cell Development

In addition to the signal transduction functions of IRFs in innate immune responses, multiple IRFs (IRF1, IRF2, IRF4, and IRF8) play essential roles in the development of immune cells, including dendritic, myeloid, natural killer (NK), B, and T cells.[3]

Dendritic cells (DC) are a group of heterogeneous cells that can be divided into different subsets with distinct functions and developmental programs. IRF4 and IRF8 specify and direct the differentiation of different subsets of DCs by stimulating subset-specific gene expression.[3] For example, IRF4 is required for the generation of CD4 + DCs, whereas IRF8 is essential for CD8α + DCs. In addition to IRF4 and IRF8, IRF1 and IRF2 are also involved in DC subset development.

IRF8 has also been implicated in the promotion of macrophage development from common myeloid progenitors (CMPs) and the inhibition of granulocytic differentiation during the divergence of granulocytes and monocytes.

IRF8 and IRF4 are also involved in the regulation of B and T-cell development at multiple stages. IRF8 and IRF4 function redundantly to drive common lymphoid progenitors (CLPs) to B-cell lineage. IRF8 and IRF4 are also required in the regulation of germinal center (GC) B cell differentiation.

Role in Diseases

IRFs are critical regulators of immune responses and immune cell development, and abnormalities in IRF expression and function have been linked to numerous diseases. Due to their critical role in IFN type I activation, IRFs are implicated in autoimmune diseases that are linked to activation of IFN type I system, such as systemic lupus erythematosus (SLE).[10] Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked to oncogenesis.[11] In addition to autoimmune diseases and cancers, IRFs are also found to be involved in the pathogenesis of metabolic, cardiovascular, and neurological diseases, such as hepatic steatosis, diabetes, cardiac hypertrophy, atherosclerosis, and stroke.[3]


See also


  1. ^ Paun A, Pitha PM (2007). "The IRF family, revisited". Biochimie. 89 (6–7): 744–53. doi:10.1016/j.biochi.2007.01.014. PMC 2139905. PMID 17399883.
  2. ^ a b Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ (December 1992). "Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes". The Journal of Biological Chemistry. 267 (35): 25589–96. PMID 1460054.
  3. ^ a b c d e f Zhao GN, Jiang DS, Li H (February 2015). "Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease". Biochimica et Biophysica Acta. 1852 (2): 365–78. doi:10.1016/j.bbadis.2014.04.030. PMID 24807060.
  4. ^ Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (December 1994). "Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma". Science. 266 (5192): 1865–9. Bibcode:1994Sci...266.1865C. doi:10.1126/science.7997879. PMID 7997879.
  5. ^ Offermann MK (2007). "Kaposi sarcoma herpesvirus-encoded interferon regulator factors". Current Topics in Microbiology and Immunology. Current Topics in Microbiology and Immunology. 312: 185–209. doi:10.1007/978-3-540-34344-8_7. ISBN 978-3-540-34343-1. PMID 17089798.
  6. ^ Moore PS, Boshoff C, Weiss RA, Chang Y (December 1996). "Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV". Science. 274 (5293): 1739–44. Bibcode:1996Sci...274.1739M. doi:10.1126/science.274.5293.1739. PMID 8939871. S2CID 29713179.
  7. ^ Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS (October 1997). "KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway". Oncogene. 15 (16): 1979–85. doi:10.1038/sj.onc.1201571. PMID 9365244.
  8. ^ Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, et al. (August 2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.
  9. ^ Shah, Masaud; Choi, Sangdun (2016), Choi, Sangdun (ed.), "Interferon Regulatory Factor", Encyclopedia of Signaling Molecules, New York, NY: Springer, pp. 1–10, doi:10.1007/978-1-4614-6438-9_101496-1, ISBN 978-1-4614-6438-9, retrieved 2021-03-08
  10. ^ Santana-de Anda K, Gómez-Martín D, Díaz-Zamudio M, Alcocer-Varela J (December 2011). "Interferon regulatory factors: beyond the antiviral response and their link to the development of autoimmune pathology". Autoimmunity Reviews. 11 (2): 98–103. doi:10.1016/j.autrev.2011.08.006. PMID 21872684.
  11. ^ Yanai H, Negishi H, Taniguchi T (November 2012). "The IRF family of transcription factors: Inception, impact and implications in oncogenesis". Oncoimmunology. 1 (8): 1376–1386. doi:10.4161/onci.22475. PMC 3518510. PMID 23243601.

External links

This article incorporates text from the public domain Pfam and InterPro: IPR001346

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Interferon regulatory factor transcription factor Provide feedback

This family of transcription factors are important in the regulation of interferons in response to infection by virus and in the regulation of interferon-inducible genes. Three of the five conserved tryptophan residues bind to DNA.

Literature references

  1. Escalante CR, Yie J, Thanos D, Aggarwal AK; , Nature 1998;1:103-106.: Structure of IRF-1 with bound DNA reveals determinants of interfereon regulation. PUBMED:9422515 EPMC:9422515

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001346

Viral infections induce the expression of type I interferons (IFN-alpha and IFN-beta) genes. The induction is due to the transcriptional activation of the IFN genes. Interferon regulatory factor I (IRF-1) is one of the transcription factors responsible for that activation. IRF-1 binds to an upstream regulatory cis element, known as the interferon consensus sequence (ICS), which is found in the promoters of type I IFN and IFN-inducible MHC class I genes. Interferon regulatory factor 2 (IRF-2) is a protein that also interacts with the ICS, but that does not function as an activator; rather, it suppresses the function of IRF-1 under certain circumstances [ PUBMED:2691585 ].

These proteins share a highly conserved N-terminal domain of about 100 amino acid residues which is involved in DNA-binding and which contain five conserved tryptophans. This domain is known as a 'tryptophan pentad repeat' or a 'tryptophan cluster' and is also present in:

  • Interferon consensus sequence binding protein (ICSBP) [ PUBMED:2111015 ], a transcription factor expressed predominantly in lymphoid tissues and induced by IFN-gamma that also binds to the ICS.
  • Transcriptional regulator ISGF3 gamma subunit [ PUBMED:1630447 ]. ISGF3 is responsible for the initial stimulation of interferon-alpha-responsive genes. It recognises and binds to the interferon-stimulated response element (ISRE) within the regulatory sequences of target genes.
  • Interferon regulatory factor 3 (IRF-3).
  • Interferon regulatory factor 4 (IRF-4) which binds to the interferon- stimulated response element (ISRE) of the MHC class I promoter.
  • Interferon regulatory factor 5 (IRF-5).
  • Interferon regulatory factor 6 (IRF-6).
  • Interferon regulatory factor 7 (IRF-7).
  • Gamma Herpesviruses vIRF-1, -2 and -3, proteins with homology to the cellular transcription factors of the IRF family [ PUBMED:10933732 ]. Neither vIRF-1 nor vIRF-2 bind to DNA with the same specificity as cellular IRFs, indicating that if vIRFs are DNA-binding proteins, their binding has a pattern distinct from that of the cellular IRFs. Whether vIRF-3 can bind DNA with the same specificity as cellular IRFs is not known.

The IRF tryptophan pentad repeat DNA-binding domain has an alpha/beta architecture comprising a cluster of three alpha-helices (alpha1-alpha3) flanked on one side by a mixed four-stranded beta-sheet (beta1-beta4). It forms a helix-turn-helix motif that binds to ISRE consensus sequences found in target promoters. Three of the tryptophan residues contact DNA by recognising a GAAA sequence [ PUBMED:9422515 ].

This entry represents the IRF tryptophan pentad repeat DNA-binding domain.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan HTH (CL0123), which has the following description:

This family contains a diverse range of mostly DNA-binding domains that contain a helix-turn-helix motif.

The clan contains the following 381 members:

AbiEi_3_N AbiEi_4 ANAPC2 AphA_like AraR_C Arg_repressor ARID ArsR B-block_TFIIIC B5 Bac_DnaA_C Baculo_PEP_N BetR BHD_3 BLACT_WH Bot1p BrkDBD BrxA BsuBI_PstI_RE_N C_LFY_FLO CaiF_GrlA CarD_CdnL_TRCF CDC27 Cdc6_C Cdh1_DBD_1 CDT1 CDT1_C CENP-B_N Costars CPSase_L_D3 Cro Crp CSN4_RPN5_eIF3a CSN8_PSD8_EIF3K CtsR Cullin_Nedd8 CUT CUTL CvfB_WH DBD_HTH DDRGK DEP Dimerisation Dimerisation2 DNA_binding_1 DNA_meth_N DpnI_C DprA_WH DsrC DsrD DUF1016_N DUF1133 DUF1153 DUF1323 DUF134 DUF1376 DUF1441 DUF1492 DUF1495 DUF1670 DUF1804 DUF1836 DUF1870 DUF2089 DUF2250 DUF2316 DUF2513 DUF2551 DUF2582 DUF3116 DUF3161 DUF3253 DUF3489 DUF3853 DUF3860 DUF3895 DUF3908 DUF433 DUF434 DUF4364 DUF4373 DUF4423 DUF4447 DUF4777 DUF480 DUF4817 DUF5635 DUF573 DUF5805 DUF6088 DUF6262 DUF6362 DUF6432 DUF6462 DUF6471 DUF722 DUF739 DUF742 DUF937 DUF977 E2F_TDP EAP30 eIF-5_eIF-2B ELL ESCRT-II Ets EutK_C Exc F-112 FaeA Fe_dep_repr_C Fe_dep_repress FeoC FokI_D1 FokI_dom_2 Forkhead FtsK_gamma FUR GcrA GerE GntR GP3_package HARE-HTH HemN_C HNF-1_N Homeobox_KN Homeodomain Homez HPD HrcA_DNA-bdg HSF_DNA-bind HTH_1 HTH_10 HTH_11 HTH_12 HTH_13 HTH_15 HTH_16 HTH_17 HTH_18 HTH_19 HTH_20 HTH_21 HTH_22 HTH_23 HTH_24 HTH_25 HTH_26 HTH_27 HTH_28 HTH_29 HTH_3 HTH_30 HTH_31 HTH_32 HTH_33 HTH_34 HTH_35 HTH_36 HTH_37 HTH_38 HTH_39 HTH_40 HTH_41 HTH_42 HTH_43 HTH_45 HTH_46 HTH_47 HTH_48 HTH_49 HTH_5 HTH_50 HTH_51 HTH_52 HTH_53 HTH_54 HTH_55 HTH_56 HTH_57 HTH_58 HTH_59 HTH_6 HTH_60 HTH_61 HTH_7 HTH_8 HTH_9 HTH_ABP1_N HTH_AraC HTH_AsnC-type HTH_CodY HTH_Crp_2 HTH_DeoR HTH_IclR HTH_Mga HTH_micro HTH_OrfB_IS605 HTH_PafC HTH_ParB HTH_psq HTH_SUN2 HTH_Tnp_1 HTH_Tnp_1_2 HTH_Tnp_2 HTH_Tnp_4 HTH_Tnp_IS1 HTH_Tnp_IS630 HTH_Tnp_ISL3 HTH_Tnp_Mu_1 HTH_Tnp_Mu_2 HTH_Tnp_Tc3_1 HTH_Tnp_Tc3_2 HTH_Tnp_Tc5 HTH_WhiA HxlR IBD IF2_N IRF KicB KilA-N Kin17_mid KORA KorB La LacI LexA_DNA_bind Linker_histone LZ_Tnp_IS481 MADF_DNA_bdg MAGE MARF1_LOTUS MarR MarR_2 MC6 MC7 MC8 MerR MerR-DNA-bind MerR_1 MerR_2 Mga Mnd1 MogR_DNAbind Mor MotA_activ MqsA_antitoxin MRP-L20 Mrr_N MukE Myb_DNA-bind_2 Myb_DNA-bind_3 Myb_DNA-bind_4 Myb_DNA-bind_5 Myb_DNA-bind_6 Myb_DNA-bind_7 Myb_DNA-binding Neugrin NFRKB_winged NOD2_WH NUMOD1 ORC_WH_C OST-HTH P22_Cro PaaX PadR PapB PAX PCI Penicillinase_R Phage_AlpA Phage_antitermQ Phage_CI_repr Phage_CII Phage_NinH Phage_Nu1 Phage_rep_O Phage_rep_org_N Phage_terminase PheRS_DBD1 PheRS_DBD2 PheRS_DBD3 PhetRS_B1 Pou Pox_D5 PqqD PRC2_HTH_1 PUFD PuR_N Put_DNA-bind_N pXO2-72 Raf1_HTH Rap1-DNA-bind Rep_3 RepA_C RepA_N RepB RepC RepL Replic_Relax RFX_DNA_binding Ribosomal_S18 Ribosomal_S19e Ribosomal_S25 Rio2_N RNA_pol_Rpc34 RNA_pol_Rpc82 RNase_H2-Ydr279 ROQ_II ROXA-like_wH RP-C RPA RPA_C RPN6_C_helix RQC Rrf2 RTP RuvB_C S10_plectin SAC3_GANP SANT_DAMP1_like SatD SelB-wing_1 SelB-wing_2 SelB-wing_3 SgrR_N Sigma54_CBD Sigma54_DBD Sigma70_ECF Sigma70_ner Sigma70_r2 Sigma70_r3 Sigma70_r4 Sigma70_r4_2 SinI SKA1 Ski_Sno SLIDE Slx4 SMC_Nse1 SMC_ScpB SoPB_HTH SpoIIID SRP19 SRP_SPB STN1_2 Stn1_C Stork_head Sulfolobus_pRN Suv3_N Swi6_N SWIRM Tau95 TBPIP TEA Terminase_5 TetR_N TFA2_Winged_2 TFIIE_alpha TFIIE_beta TFIIF_alpha TFIIF_beta Tn7_Tnp_TnsA_C Tn916-Xis TraI_2_C Trans_reg_C TrfA TrmB tRNA_bind_2 tRNA_bind_3 Trp_repressor UPF0122 UPF0175 Vir_act_alpha_C XPA_C Xre-like-HTH YdaS_antitoxin YidB YjcQ YokU z-alpha


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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: [1]
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Bateman A
Number in seed: 73
Number in full: 3941
Average length of the domain: 101.90 aa
Average identity of full alignment: 47 %
Average coverage of the sequence by the domain: 25.53 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.9 27.1
Noise cut-off 26.7 26.3
Model length: 106
Family (HMM) version: 20
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IRF domain has been found. There are 43 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2K1F1 View 3D Structure Click here
A0A0R4IBK0 View 3D Structure Click here
A0FIN4 View 3D Structure Click here
A8B8L1 View 3D Structure Click here
A8E5I1 View 3D Structure Click here
B0S682 View 3D Structure Click here
B7SEE0 View 3D Structure Click here
D3ZEX6 View 3D Structure Click here
D3ZPU1 View 3D Structure Click here
D4AAV0 View 3D Structure Click here
F1Q573 View 3D Structure Click here
F1Q8A2 View 3D Structure Click here
F1QDN4 View 3D Structure Click here
F1QNG2 View 3D Structure Click here
F1QPF2 View 3D Structure Click here
F7FGY2 View 3D Structure Click here
G3V8J4 View 3D Structure Click here
O14896 View 3D Structure Click here
P10914 View 3D Structure Click here
P14316 View 3D Structure Click here
P15314 View 3D Structure Click here
P23570 View 3D Structure Click here
P23611 View 3D Structure Click here
P23906 View 3D Structure Click here
P56477 View 3D Structure Click here
P70434 View 3D Structure Click here
P70671 View 3D Structure Click here
P97431 View 3D Structure Click here
Q00978 View 3D Structure Click here
Q02556 View 3D Structure Click here
Q08DD6 View 3D Structure Click here
Q13568 View 3D Structure Click here
Q14653 View 3D Structure Click here
Q15306 View 3D Structure Click here
Q3SZP0 View 3D Structure Click here
Q4JF28 View 3D Structure Click here
Q58DJ0 View 3D Structure Click here
Q5NUI4 View 3D Structure Click here
Q5PNN7 View 3D Structure Click here
Q5XIB0 View 3D Structure Click here