Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Orphanet Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol IRAK4 contributors: mct/ - updated : 12-07-2018
HGNC name interleukin-1 receptor-associated kinase 4
HGNC id 17967
DNA
TYPE functioning gene
STRUCTURE 30.60 kb     12 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status provisional
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
12 - 4771 - 336 - 2009 19181383
13 - 4351 51.4 460 - 2009 19181383
12 - 4205 37.5 336 - 2009 19181383
12 - 4303 51.4 460 - 2009 19181383
11 - 4157 37.5 336 - 2009 19181383
10 - 3987 37.5 336 - 2009 19181383
13 - 4525 - 460 - 2009 19181383
13 - 4544 - 336 - 2009 19181383
11 - 4245 - 257 - 2009 19181383
14 - 4408 - 336 - 2009 19181383
13 - 4360 - 336 - 2009 19181383
11 - 4061 - 257 - 2009 19181383
12 - 4190 - 336 - 2009 19181383
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveliver   highly
Urinarykidney   highly
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N terminal death domain, and N-terminal loop of IRAK4 that plays a critical regulatory role in Myddosome assembly
  • kinase catalytic domain
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Drosophila pelle
    Homologene
    FAMILY
  • protein kinase superfamily
  • TKL Ser/Thr protein kinase family
  • Pelle subfamily
  • IRAK family
  • CATEGORY antigen , receptor membrane serine/threonine
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    text
  • in unstimulated cells endogenous IRAK4 is distributed in the cytosol and the protein kinase activity is inhibited
  • basic FUNCTION
  • central element in the early signal transduction of Toll/IL1R (TIR) upstream of IRAK1
  • required for various responses induced by IL-1R and Toll-like receptor signals
  • required for the optimal transduction of IL1-induced signals, including the activation of IRAK1, NF-kappaB, and JNK, and the maximal induction of inflammatory cytokines
  • plays a critical role in IL1 receptor (IL1R)/TLR7-mediated induction of inflammatory responses
  • initiate a cascade of signaling events eventually leading to induction of inflammatory target gene expression
  • plays an important role in innate and adaptive immune responses
  • its kinase activity is required for IRAK4-dependent signaling in innate and adaptive immunity
  • protein kinases that mediate signaling by Toll/IL1/Plant R (TIR) domain-containing receptors including the IL-1, IL-18, and Toll-like receptors (TLRs)
  • its non-kinase functions are essential in cells, whereas the kinase activity of IRAK4 appears redundant with that of IRAK1
  • having a kinase activity that is critical for development of atherosclerosis
  • has an ability to induce the degradation of IRAK1 in addition to its role as an activator of IRAK1
  • induce the degradation of IRAK1 in a proteosome-independent manner
  • MYD88 and the associated kinases IRAK1 and IRAK4 are essential for activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) survival
  • IRAK4 activation acts normally to regulate microglial activation status and influence amyloid homeostasis in the brain
  • serine/threonine kinase that is a central adaptor protein in TLR signaling
  • unexpected role of IRAK4, AKT1, and MTOR in the regulation of tolerance in human monocytes
  • IRAK4 is recruited to the membrane-proximal adaptor MYD88 through death domain (DD) interactions, forming the oligomeric Myddosome and mediating NFKB1 activation
  • in pericytes, MYD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic
  • kinase activity of IRAK4 plays a critical role in signalling mediated by the TLRs
  • mediates host defense against infections
  • plays a critical role in innate immune signaling by Toll-like receptors (TLRs), and loss of IRAK4 activity increases susceptibility to bacterial infections and causes defects in TLR and IL1 ligand sensing
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS immunity/defense
    text innate immunity
    PATHWAY
    metabolism
    signaling signal transduction
    part of the IL1R signaling cascade and is capable of transmitting signals both dependent on and independent of its kinase activity
    a component
  • heterodimer with IRAK1, IRAK2
  • essential component of the signal transduction complex downstream of the IL1 and Toll-like receptors
  • MYD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MYD88, 4 IRAK4 and 4 IRAK2 DDs
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with IRAK1 and TRAF6 in an IL-1 dependent manner, activating NF-K beta and mitogen-activated protein (MAP) kinase pathway
  • activating PELI1, PELI2, PELI3
  • TIRAP is a substrate for IRAK1 and IRAK4 and is likely an important control mechanism in TLR2 and TLR4 signal transduction
  • IRAK1 catalytic activity is not triggered by a covalent modification but by an allosteric mechanism induced by its interaction with IRAK4
  • IRAK4 kinase activity controls the activation of IRF5, a transcription factor implicated in the pathogenesis of multiple autoimmune diseases
  • IRAK4 activity regulates likely MAP3K7 and IKBKB activation, leading to the nuclear translocation of IRF5 and induction of inflammatory cytokines in human monocytes
  • cell & other
    REGULATION
    inhibited by MYD88 (requires activation of the MyD88-dependent pathway and the death domains of both MyD88 and IRAK4 are important for this downregulation)
    ASSOCIATED DISORDERS
    corresponding disease(s) IRAK4D
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    in pyogenic bacterial infections
    Susceptibility to pyogenic bacterial infections
    Variant & Polymorphism other mutations associated with pyogenic bacterial diseases, including invasive pneumococcal diseases
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascularatheroma 
    potential therapeutic target in atherogenesis
    miscelleaneoustransplantation 
    elucidation of the role of IRAK4 kinase activity in adaptive immunity might also open new opportunities for future treatment modalities in transplantation
    cancerhemopathy 
    development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations
    osteoarticularbone 
    is a potential therapeutic target to inhibit stimulated osteoclastogenesis
    ANIMAL & CELL MODELS
    IRAK4(-/-) animals are severely impaired in their response to viral and bacterial challenges