Interleukin-1 receptor-associated kinase 4 (IRAK4)

The protein contains 460 amino acids for an estimated molecular weight of 51530 Da.

 

Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections. (updated: Jan. 31, 2018)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology.


Interpro domains
Total structural coverage: 68%
Model score: 35

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VariantDescription
No effect on inhibition of NF-kappa-B activation
No effect on inhibition of NF-kappa-B activation
dbSNP:rs142376871
dbSNP:rs4251583
dbSNP:rs55944915
dbSNP:rs4251545
IMD67
Increases inhibition of NF-kappa-B complex activation
No effect on inhibition of NF-kappa-B activation
No effect on inhibition of NF-kappa-B activation
IMD67

The reference OMIM entry for this protein is 606883

Interleukin 1 receptor-associated kinase 4; irak4
Ren64

DESCRIPTION

Interleukin-1 receptor (see IL1R; 147810)-associated kinases (e.g., IRAK1; 300283) are important mediators in the signal transduction of Toll-like receptor (TLR, e.g., TLR4; 603030) and IL1R family members, collectively referred to as TIRs. IRAK4 functions in this signal transduction pathway (Li et al., 2002).

CLONING

By SEREX (serologic analysis of recombinant cDNA expression libraries) screening of renal tumors, Scanlan et al. (1999) identified multiple antigens, including REN64. The deduced 460-amino acid protein is strongly expressed in kidney, as determined by immunohistochemistry. RT-PCR analysis detected expression in all 6 tissues tested (lung, testis, small intestine, breast, liver, and placenta). By database searching for IRAK-like sequences and PCR of a universal cDNA library, Li et al. (2002) obtained a cDNA encoding IRAK4, which is 98% identical to REN64. The predicted protein is 84% identical to the mouse protein and, like IRAK1, IRAK2 (603304), IRAKM (604459), and the Drosophila Pelle protein, it has an N-terminal death domain and a central kinase domain. Unlike the other IRAK proteins, however, but similar to Pelle, IRAK4 has a short C-terminal domain. Northern blot analysis revealed expression of 3.0- and 4.4-kb transcripts, with strongest expression in kidney and liver. RT-PCR analysis detected wide, low-level expression of IRAK4.

MAPPING

Scott (2002) mapped the REN64/IRAK4 gene to chromosome 12 based on similarity between the REN64 sequence (GenBank GENBANK AF155118) and a chromosome 12 clone (GenBank GENBANK AC093012). Gross (2011) mapped the IRAK4 gene to chromosome 12q12 based on an alignment of the IRAK4 sequence (GenBank GENBANK AF155118) with the genomic sequence (GRCh37).

GENE FUNCTION

Functional analysis by Li et al. (2002) determined that IRAK4, like IRAK1 and Pelle, has auto- and cross-phosphorylation kinase activity. Precipitation and binding analyses showed weak interaction between IRAK4 and IRAK1, but IRAK4 did not interact with other IRAK family members. Overexpressed IRAK4 interacted with MYD88 (602170) and TRAF6 (602355) and activated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NFKB; 164011) pathways. Endogenous IRAK4 associated in a transient IL1 (see 147720)-dependent manner with unmodified IRAK1 and TRAF6. Luciferase reporter analysis showed that IRAK4 lacking the kinase domain inhibited IL1- but not tumor necrosis factor (TNF; 191160)- induced NFKB and IRAK1 activation. SDS-PAGE and autoradiographic analysis indicated that IRAK4 phosphorylates and activates IRAK1 at thr387, but not vice versa. Li et al. (2002) proposed that IRAK4 acts upstream of other IRAKs and may function as an IRAK1 kinase, triggering a cascade of phosphorylation events. Yang et al. (2005) found that production of IFNA (147660)/IFNB (147640) and IFNL (IL29; 607403) in response TLR7 (300365), TLR8 (600366), and TLR9 (605474) stimulation was abolished in IRAK4-deficient blood cells (see 607676). However, IFNA/IFNB and IFNL production in response to 9 of 11 viruses was normal or weakly affected in IRAK4-deficient blood cells. Stimulation with TLR3 (603029) and TLR4 agonists induced normal levels of these interferons in IRAK4-deficient blood cells, suggesting that IRAK4-deficient patients may use these TLRs or a TLR-independent mechanism to control viral infections. Suzuki et al. (2006) found that Irak4 was critical for several T-cell functions in mice ... More on the omim web site

Subscribe to this protein entry history

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606883 was added.

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed